8-phenyl-isoquinolines and pharmaceutical composition thereof used in the treatment of irritable bowel syndrome

ABSTRACT

A series of 8-phenyl-isoquinoline derivatives (I) exhibit high binding affinity to 5-HT 7  receptor (5-HT7R) and demonstrate potent antinociceptive activity in two animal models for Irritable Bowel Syndrome (IBS) by intraperitoneal injection (i.p.) or by oral administration (p.o.). These 5-HT 7  receptor antagonists are a new class of therapeutic agents for the treatment of IBS.

CROSS-REFERENCES TO RELATED APPLICATIONS

This patent application is a U.S. National Stage Application of PCT/CA2018/000043 filed Mar. 02, 2018 and claims the benefit of priority from U.S. Provisional Application Ser. No. 62/466,370, filed Mar. 3, 2017, the contents of each of which is incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a series of 8-phenylisoquinoline derivatives used in the treatment of irritable bowel syndrome (IBS).

BACKGROUND OF THE INVENTION

The 5-HT7 receptor (5-HT₇R) is the latest member among the 14 subtypes in 5-HT receptor family. It is widely distributed in both central nervous system (CNS) (most abundant in hypothalamus, thalamus, hippocampus, and cortex) and peripheral organs (e.g. spleen, kidney, intestine, heart and coronary artery), which implicates its role in various physiological functions and pathologic processes. 5-HT₇R is positively coupled to adenylate cyclase and has a low sequence homology with other 5-HT receptor subtypes (less than 40%). Based on the studies conducted by using selective 5-HT₇R ligands and knock-out mice models, 5-HT₇R is involved in circadian rhythm regulation, thermoregulation, sleep disorders, mood disorders, pain, learning and memory. Therefore, the 5-HT₇R ligands are potential therapeutic agents for the treatment of a variety of 5-HT₇R-related diseases and disorders. The 5-HT₇R antagonists may be effective treatment of depression, anxiety, schizophrenia, and dementia, whereas the 5-HT₇R agonists could be potential treatment for pain and symptoms of pain (especially neuropathic pain and inflammatory pain).

In addition, 5-HT₇R is also a potential drug target for migraine (WO2009029439 A1), hypertention, various mucosal inflammation (WO2012058769 A1), such as irritable bowel syndrome, and urinary incontinence, through its effective smooth muscle relaxation of central and peripheral blood vessels and intestinal, colon, and bladder tissues, respectively. Several therapeutic agents, such as tricyclic antidepressants, typical and atypical antipsychotics and some 5-HT₂ receptor antagonists, were found to display moderate to high affinity for 5-HT₇R.

In consideration of the versatile therapeutic potential of 5-HT₇R ligands, numerous efforts have been focused on the discovery and development of selective 5-HT₇R agonists and antagonists. Different structural classes of 5-HT₇R ligands have been reported, including 5-HT₇R agonists, such as AS-19, LP-44, LP-12, LP-211, and E-55888, and 5-HT₇R antagonists, such as SB-258719, SB-269970, SB-656104, DR-4004 and JNJ-18038683. Despite of the numerous efforts, there is no 5-HT₇R ligand has been used in clinic and still a need to discover and develop novel 5-HT₇R ligands with desirable physicochemical and pharmacokinetic properties as potential therapeutic agents for the treatment of 5-HT₇R-related diseases and disorders.

Irritable bowel syndrome (IBS) is mainly characterized by recurrent abdominal pain associated with bowel habit changes, in the absence of identifiable organic cause or macroscopic lesions. IBS represents a substantial clinical problem that accounts for 10-40% of gastroenterology outpatients in Asian and Western countries. Severe abdominal pain is the clinical hallmark of IBS, the most likely symptom to result in medical consultation. Subtypes of IBS include diarrhea-predominant IBS-D, constipation predominant IBS-C, or alternating IBS-A. The development of IBS disorder is believed to be related to a disturbed brain-gut axis; however, the pathogenesis is still poorly understood.

Altered intestinal serotonin (5-HT) level in patients is a validated biomarker for IBS. However, clinical drugs targeting 5-HT receptors for IBS treatment are limited nowadays and prescribed only under emergency investigational drug protocol. Alosetron, a 5-HT₃R antagonist for treatment of IBS-D, had been withdrawn by FDA for severe side effects (e.g. ischemic colitis, cerebrovascular or cardiovascular ischemia), and reintroduced later for women only with severe symptoms. Other available symptom-relieving agents (e.g. antispasmodics, antidiarrheals, osmotics, sedatives, antidepressants etc.) are not globally effectively for patients. Medical research for IBS pathogenesis relies heavily on analysis of patient biopsy samples. Animal models with visceral hypersensitivity have been established, albeit each with weaknesses and strengths regarding its translational value to IBS. As such, progress in therapeutic development for IBS has been hindered. To date, development of novel targeted drugs for clinical management of IBS is much in need.

Diverse risk factors, including psychological stress, intestinal infection, immune and inflammatory responses, genetic predisposition, and changes in the gut microbiota, have been found to contribute to the development of IBS symptoms. A high rate of IBS patients reported past traumatic events in childhood or adulthood. IBS symptoms may begin after a bout of infectious gastroenteritis, termed post-infectious (PI)-IBS. Follow-up studies of a waterborne giardiasis outbreak in Norway reported that more than 40% of patients experience IBS-like symptoms lasting for three years after acute Giardia lamblia infection. The post-infective symptom exacerbation was correlated with the experience of physical or mental stress. Experimental models of post-clearance of pathogen infection and post-resolution of chemical-induced enterocolitis exhibited intestinal hyperalgesia. Moreover, animals subjected to psychological stress also showed visceral hypersensitivity to colorectal distension. Two mouse models with IBS-like visceral hypersensitivity, including dual challenge with Giardia postinfection combined with psychological stress and post-resolution of trinitrobenzene sulfonic acid (TNBS)-induced colitis were used for testing of the analgesic effects of novel 5-HT₇R ligands.

Among the receptor subtypes, 5-HT₇R is the most recently discovered family member with unknown pathophysiological role. Stimulation of 5-HT₇R induces exaggerated relaxation of circular smooth muscle, which has been implicated in ineffective gas propulsion and abdominal bloating. Expression of 5-HT₇R has been identified in the enteric neurons (i.e. myenteric afferent neurons and mucosal nerve fibers), smooth muscles, and dendritic cells in the colon, as well as lumbar dorsal root ganglions and brain. The present invention proves a series of 8-phenylisoquinoline derivatives, on alleviation of intestinal pain in two animal models of IBS.

SUMMARY OF THE INVENTION

The present invention relates to a novel compound of the following general formula or a pharmaceutically acceptable salt thereof:

wherein R₁ is selected from a group consisting of hydrogen, a C₁₋₁₀ linear chain alkyl group, a C₁₋₁₀ branched chain alkyl group, a (CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and a (CH₂)_(n)ArR₁₀R₁₁R₁₂, wherein the n is an integer from 0 to 6, Hete is a heteroaromatic group, Ar is an aromatic group, and R₁₀, R₁₁ and R₁₂ are independently selected from a group consisting of hydrogen, halo group, a nitro group, an amino group, a cyano group, an acetyl group, a C₁₋₆ linear chain saturated alkyl group, a C₁₋₆ linear chain saturated alkoxy group and a C₁₋₆ linear chain saturated haloalkyl group;

R₂ is a hydrogen or a C₁₋₆ linear chain saturated alkyl group; and

X₁, X₂, X₃, X₄ and X₅ are independently selected from a group consisting of hydrogen, a halo group, a nitro group, an amino group, a cyano group, an acetyl group, a C₁₋₆ linear chain saturated alkyl group, a C₁₋₆ branched chain saturated alkyl group, a C₁₋₆ linear chain saturated alkoxy group, a C₁₋₆ branched chain saturated alkoxy group, a C₁₋₆ linear chain saturated alkylthio group, a C₁₋₆ branched chain saturated alkylthio group, a C₁₋₆ linear chain saturated haloalkyl group and a C₁₋₆ branched chain saturated haloalkyl group.

The present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of this novel compound or a pharmaceutically acceptable salt thereof. Further, the present invention relates to a method of using the aforementioned pharmaceutical composition in the treatment of irritable bowel syndrome.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the synthetic scheme 1 of novel derivatives of 8-phenylisoquinoline;

FIG. 2 shows the synthetic scheme 2 of novel derivatives of 8-phenylisoquinoline;

FIG. 3 shows the synthetic scheme 3 of novel derivatives of 8-phenylisoquinoline;

FIG. 4 shows the synthetic scheme 4 of novel derivatives of 8-phenylisoquinoline;

FIG. 5 shows the visceral hypersensitivity observed in an IBS-like mouse model by dual challenge of Giardia combined with stress. FIG. 5(A) The visceromoter response (VMR) to colorectal distension was expressed as area under curve (AUC) and determined in each mouse as an indicator of intestinal pain. FIG. 5(B) Representative images of colon histology in PN and GW mice. FIG. 5(C) Representative images of immunostained 5-HT₇R in colonic tissues of PN and GW mice (panel a) and quantification of 5-HT₇R immunoreactivity in muscle/nerve and mucosal layers (panel b and c). FIG. 5(D) The results of Western blotting showing increased 5-HT₇R protein levels in GW mice.

FIG. 6 shows the visceral hypersensitivity noted in an IBS-like mouse model following resolution of TNBS-induced colitis. FIG. 6(A) The visceromoter response (VMR) to colorectal distension was expressed as area under curve (AUC), and was determined in each mouse as an indicator of intestinal pain. FIG. 6(B) Intestinal myeloperoxidase (MPO) activity was examined as an indicator of inflammatory leukocyte activation. FIG. 6(C) Histopathological score of colonic tissues in mice. FIG. 6(D) Representative images of colon histology in sham and TNBS mice. FIG. 6(E) Immunostaining of 5-HT₇R in colonic tissues of sham and TNBS-d24 mice. Representative images of 5-HT₇R staining (panel a) and quantification of 5-HT₇R immunoreactivity in muscle/nerve and mucosal layers (panel b and c). FIG. 6(F) The protein levels of 5-HT₇R in mouse colon. (G) The transcript levels of 5-HT₇R in mouse colon.

FIG. 7 shows the anti-nociceptive effects of a SHT₇R antagonist SB269970 (SB7) in an IBS-like mouse model.

FIG. 8 shows the analgesic effects of oral administration of novel 8-phenylisoquinoline derivatives in GW mice.

FIG. 9 shows dose and time response of compound 8 in intestinal pain of GW mice. FIG. 9(A) Compound 8 was i.p. administered at various doses 90 minutes before pain analysis. FIG. 9(B) Compound 8 was p.o. administered at various doses 90 minutes before pain analysis. FIG. 9(C) Compound 8 (5 mg/Kg) was p.o. administered at 1.5, 4 or 12 hours before pain analysis. FIG. 9(D) Compound 8 (3 mg/Kg) was repeatedly administered p.o. over a course of 10 days as multiple doses (m.d.) before pain analysis.

FIG. 10 shows the anti-nociceptive effects of 8-phenylisoquinoline derivatives in TNBS mice.

FIG. 11 shows the comparison of analgesic effects and adverse response to compound 8 and reference standards in GW and TNBS mice. FIG. 11(A) Intestinal pain levels in GW mice. FIG. 11(B) Intestinal pain levels in TNBS mice. FIG. 11(C) Representative photoimages of colonic histology of each treatment group. Hyperemia (*) and granulocyte infiltration (arrowheads) were observed in the ALN group but not others.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel compound of the following general formula or a pharmaceutically acceptable salt thereof:

wherein R₁ is selected from a group consisting of hydrogen, a C₁₋₁₀ linear chain alkyl group, a C₁₋₁₀ branched chain alkyl group, a (CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and a (CH₂)_(n)ArR₁₀R₁₁R₁₂, wherein n is an integer from 0 to 6, Hete is a heteroaromatic group, Ar is an aromatic group, and R₁₀, R₁₁ and R₁₂ are independently selected from a group consisting of hydrogen, a halo group, a nitro group, an amino group, a cyano group, an acetyl group, a C₁₋₆ linear chain saturated alkyl group, a C₁₋₆ linear chain saturated alkoxy group and a C₁₋₆ linear chain saturated haloalkyl group;

R₂ is a hydrogen or a C₁₋₆ linear chain saturated alkyl group; and

X₁, X₂, X₃, X₄ and X₅ are independently selected from a group consisting of hydrogen, a halo group, a nitro group, an amino group, a cyano group, an acetyl group, a C₁₋₆ linear chain saturated alkyl group, a C₁₋₆ branched chain saturated alkyl group, a C₁₋₆ linear chain saturated alkoxy group, a C₁₋₆ branched chain saturated alkoxy group, a C₁₋₆ linear chain saturated alkylthio group, a C₁₋₆ branched chain saturated alkylthio group, a C₁₋₆ linear chain saturated haloalkyl group and a C₁₋₆ branched chain saturated haloalkyl group.

In one embodiment of the present invention, the halo group of the novel compound is selected from a group consisting of fluorine, chlorine, bromine and iodine. In another embodiment of the present invention, the heteroaromatic group of the novel compound is selected from a group consisting of a pyrrolyl group, a furanyl group, a thiophenyl group, a pyridinyl group, a pyrimidinyl group, a thiazolyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzofuranyl group, an isobenzofuranyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl group and a benzothiazolyl group.

In a preferred embodiment of the present invention, the novel compound is one selected from 6-methoxy-8-(2-methoxyphenyl)-2-(3-(4-nitrophenyl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (compound 7), 6-methoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-4-yl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (compound 8), 6-methoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-3-yl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (compound 9), and 6,7-dimethoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-4-yl)propyl)-1,2,3,4-tetrahydroisoquinoline (compound 10), or a pharmaceutically acceptable salt. In a more preferred embodiment of the present invention, the novel compound is 6-methoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-4-yl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (compound 8) or a pharmaceutically acceptable salt.

The present invention further provides a pharmaceutical composition comprising: a pharmaceutically acceptable carrier, and a therapeutically effective amount of a novel compound of the following general formula:

wherein R₁ is selected from a group consisting of hydrogen, a C₁₋₁₀ linear chain alkyl group, a C₁₋₁₀ branched chain alkyl group, (CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and (CH₂)_(n)ArR₁₀R₁₁R₁₂, wherein n is an integer from 0 to 6, Hete is a heteroaromatic group, Ar is an aromatic group, and R₁₀, R₁₁ and R₁₂ are independently selected from a group consisting of hydrogen, a halo group, a nitro group, an amino group, a cyano group, an acetyl group, a C₁₋₆ linear chain saturated alkyl group, a C₁₋₆ linear chain saturated alkoxy group and a C₁₋₆ linear chain saturated haloalkyl group;

R₂ is a hydrogen or a C₁₋₆ linear chain saturated alkyl group; and

X₁, X₂, X₃, X₄ and X₅ are independently selected from a group consisting of hydrogen, a halo group, a nitro group, an amino group, a cyano group, an acetyl group, a C₁₋₆ linear chain saturated alkyl group, a C₁₋₆ branched chain saturated alkyl group, a C₁₋₆ linear chain saturated alkoxy group, a C₁₋₆ branched chain saturated alkoxy group, a C₁₋₆ linear chain saturated alkylthio group, a C₁₋₆ branched chain saturated alkylthio group, a C₁₋₆ linear chain saturated haloalkyl group and a C₁₋₆ branched chain saturated haloalkyl group.

In one embodiment of the present invention, the halo group of the novel compound of the pharmaceutical composition is selected from a group consisting of fluorine, chlorine, bromine and iodine. In another embodiment of the present invention, the heteroaromatic group of the novel compound of the pharmaceutical composition is selected from a group consisting of a pyrrolyl group, a furanyl group, a thiophenyl group, a pyridinyl group, a pyrimidinyl group, a thiazolyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzofuranyl group, an isobenzofuranyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl group and a benzothiazolyl group.

In a preferred embodiment of the present invention, comprising: a pharmaceutically acceptable carrier, and a therapeutically effective amount of 6-methoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-4-yl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (compound 8) or a pharmaceutically acceptable salt thereof.

The “pharmaceutically acceptable carrier” or “excipient” or “pharmaceutically acceptable carrier or excipient” or “bioavailable carrier” or “bioavailable carrier or excipient” includes but not limited to a solvent, a dispersant, a coating, an antimicrobial agent, an antifungal agent to preserve or a delay-absorbed agent and any other known compound to prepare formulation. In general, these carriers or excipients themselves do not have activity of treating disease. Pharmaceutical compositions or formulations prepared by using the novel compound or its derivatives disclosed in the present invention in combination with a pharmaceutically acceptable carrier or excipient do not cause adverse effect, allergy or other inappropriate reaction of animals or humans. Therefore, the novel compound or its derivatives disclosed in the present invention in combination with a pharmaceutically acceptable carrier or excipient can be applied to human clinically. The pharmaceutical compositions or formulations comprising the novel compound or its derivatives of the present invention can achieve therapeutic effect through intravenous injection, oral administration, inhalation or through local administration of nose, rectum, vagina or hypoglottis. In one embodiment, 0.1 mg to 100 mg of the active ingredient of the compound per day is administered to patients having different diseases.

The carrier to be used is different depending on the pharmaceutical composition or formulation to be prepared. The composition for sterile injection can be suspended in sterile intravenous injection diluents or solvents, such as 1,3-butanediol. The acceptable carrier could be mannitol or water. In addition, the oil fixed or synthesized monoglyceride/diglyceride suspension medium are commonly used solvents. Fatty acids, such as oleic acid, olive oil, castor oil, glyceride derivatives, especially the polyoxyethylenated form could be prepared for injection and natural pharmaceutically acceptable oil. These oil solutions or suspensions include long-chain alcohol diluents, dispersant, carboxymethyl cellulose or similar dispersant. Other surfactants for common use include Tween, Spans, other similar emulsifier, pharmaceutically acceptable solid for pharmaceutical manufacture industry, liquid, or other bioavailable enhancer for formulation development.

The composition for oral administration is adapted to oral acceptable composition or formulation, wherein the types include capsule, lozenge, troche, emulsifier, liquid suspension, dispersant and solvent. The common carrier used for oral administration such as lozenge, for example, can be lactose, corn starch, lubricant, magnesium stearate as basic additives. The diluents used for capsule include lactose, dry corn starch. The preparation for liquid suspension or emulsifier formulation is to suspend or dissolve active ingredients with binding emulsifiers or oil interface of suspending agent. Sweetening agents, flavoring agents or coloring matters can also be included.

The aerosol spray for oral use or inhalation composition is prepared by known formulation technologies. For example, the composition is dissolved in physiological saline, added with benzyl alcohol, other suitable preservatives or absorbefacients to enhance bioavailable properties. The composition of the compound provided by the present invention can also be prepared as a suppository which is administered through rectum or vagina.

The injections include hypodermic, peritoneal cavity, vein, muscle, joint cavity, intracranial, synovial fluid, intrathecal injection, aorta injection, thoracic injection, lesion injection or other suitable administration technologies.

Furthermore, the present invention provides a method for treating irritable bowel syndrome, comprising the step of administering to a subject in need thereof an effective amount of the aforementioned pharmaceutical composition. In one embodiment of the present invention, the halo group of the pharmaceutical composition is selected from a group consisting of fluorine, chlorine, bromine and iodine. In another embodiment of the present invention, the heteroaromatic group of the pharmaceutical composition is selected from a group consisting of a pyrrolyl group, a furanyl group, a thiophenyl group, a pyridinyl group, a pyrimidinyl group, a thiazolyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzofuranyl group, an isobenzofuranyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl group and a benzothiazolyl group, providing an antagonism to a 5-HT₇ receptor.

In another embodiment of the present invention, the irritable bowel syndrome is treated by providing an antagonism to 5-HT₇ receptors. In yet another embodiment of the present invention, the irritable bowel syndrome comprises a pain induced by infection followed by stress and a pain induced by chemically induced inflammation.

In yet another embodiment of the present invention, the irritable bowel syndrome is treated by inhibiting a pain induced by infection followed by stress. In another embodiment of the present invention, the irritable bowel syndrome is treated by inhibiting a pain induced by chemically induced inflammation.

The above aspects and advantages of the present invention will become apparent to those ordinarily skilled in the art after reviewing the detailed descriptions and accompanying drawing.

EXAMPLES

The present invention will now be described more specifically with reference to the following examples. It is to be noted that the following descriptions of this invention are presented herein for the purposes of illustration and description only; it is not intended to be exhaustive or to be limited to the precise form disclosed.

The present invention provides a library of novel derivatives of 8-phenylisoquinoline. The synthesis includes the following 4 schemes.

Scheme 1 (as shown in FIG. 1): The N-phenylethyl-substituted 8-phenyl-tetrahydroisoquinolin-7-ol derivatives were synthesized starting from the commercially available 7-hydroxy-6-methoxy-3,4-dihydroisoquinoline (compound 20) as depicted in FIG. 1. N-alkylation of compound 20 with phenylethyl bromide followed by NaBH₄ reduction provided amine 21. Treatment of phenethylamine 21 with Pb(OAc)₄ followed by aromatic substitution with HBr produced 8-bromo-tetrahydroisoquinoline 22. The desired target compounds 29-45 were then synthesized from 22 with various substituted-arylboranes using Suzuki coupling reaction condition in moderate yields.

Scheme 2 (as shown in FIG. 2): The N-substituted 8-(2,4-dimethoxyphenyl)-tetrahydroisoquinolin-7-ols were also prepared starting from the commercially available compound 20 as shown in Scheme 2. Treatment of compound 20 with various halides followed by NaBH₄ reduction yielded N-substituted tetrahydroisoquinolin-7-ols 11, and 61-75. Oxidation of compounds 11, and 61-75 with Pb(OAc)4 in acetic acid followed by TFA-catalyzed aromatic substitution with 1,3-dimethoxybenzene afforded the corresponding N-substituted 8-(2,4-dimethoxyphenyl)-6-methoxy-tetrahydroisoquinolin-7-ols 6, and 101-125, respectively.

Scheme 3 (as shown in FIG. 3): Treatment of compound 20 with various 3-arylpropyl bromides followed by NaBH₄ reduction provided the corresponding N-3-arylpropyl-substituted tetrahydroisoquinolin-7-ol derivatives 12-14 and 78 as depicted in Scheme 3. Bromides 15-17 and 98 were obtained by treatment of compounds 12-14 and 78 with Pb(OAc)₄ followed by aromatic substitution with HBr, respectively. O-Methylation of phenols 16 with methyl iodide in the presence of NaH yielded 6,7-dimethoxy-tetrahydroisoquinoline 18. Aryl coupling reaction of compounds 15-18 and 98 under Suzuki reaction condition with various substituted-arylboranes afforded the N-3-arylpropyl-substituted 6-methoxy-8-phenyl-tetrahydroisoquinolin-7-ols 7-10 and 142 in moderate yields, respectively.

Scheme 4 (as shown in FIG. 4): The N-phenylethyl-substituted 6,7-dimethoxy-8-phenyl-tetrahydroisoquinoline derivatives 157-173 were prepared using N-phenylethyl-substituted 8-bromo-6-methoxy-tetrahydroisoquinolin-7-ols 60-96 as depicted in Scheme 4. O-Methylation of phenols 60-96 with methyl iodide in the presence of NaH gave 6,7-dimethoxy-tetrahydroisoquinolines 150-154, respectively. Aryl coupling reaction of compounds 150-154 with various substituted-arylboranes under Suzuki reaction condition furnished 6,7-dimethoxy-8-phenyl-tetrahydroisoquinolines 157-173, respectively.

The specific synthesizing steps of those compounds depicted in the above schemes 1-4 are as follows:

Compound 21: A mixture of compound 20 (100 mg, 0.56 mmol), 2-phenylethyl bromide (311 mg, 1.68 mmol), and 2-propanol (3.5 mL) was refluxed for 15 hours. The resulting solution was concentrated and MeOH (5 mL) was added to dissolve the residue. The solution was cooled in an ice-bath and then NaBH₄ (49 mg, 1.29 mmol) was added slowly under N2. The mixture was stirred for another 10 minutes and then concentrated. The residue was treated with H₂O (20 mL) and CHCl₃ (20 mL), and then the organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated. The crude residue was chromatographed (silica gel, MeOH/CH₂Cl₂=1/100) to afford compound 21 as a white solid (146 mg, 0.52 mmol, 92%).

Compound 30: To a solution of C₁₈H₂₀BrNO₂ (50 mg, 0.14 mmol) in 2-propanol (2.0 mL) in a 10-mL thick walled Pyrex reaction vessel, 4-methoxyphenylboronic acid (26 mg, 0.19 mmol) was added. After stirring for 30 min, Pd(OAc)₂ (1.3 mg , 0.006 mmol), PPh₃ (4.7 mg, 0.02 mmol), 2 M Na₂CO_(3(aq)) (0.09 mL, 0.17 mmol), and H₂O (0.1 mL) were added. Then the mixture was heated at 140° C. for 10 min in a microwave synthesizer, and H₂O (0.35 mL) was added before cooling to room temperature. The resulting solution was diluted with H₂O (5 mL) and extracted with EtOAc (5 mL). The organic layer was washed with 5% NaHCO_(3(aq)) and brine. The organic solution was treated with Darco G-60 (100 mg) and stirred at room temperature for 30 min, and then dried over MgSO₄, filtered (the sintered glass funnel was charged with Celite to a depth of 1 cm and Florisil was spread evenly on the top of the Celite), and evaporated. The crude residue was chromatographed (silica gel, EtOAc/n-hexane=2/1) to afford an orange oil (40 mg, 0.10 mmol, 73%).

Compounds 29 and 31-40: Table 1 is a parameter table. “Parameter 1” was added into the reaction vessel for microwave-assisted heating and dissolved with “parameter 2” mL 2-propanol. The appearance of the solution was “parameter 3” and the reagent “parameter 4” was added thereinto, and stirred for “parameter 5” minutes. The appearance of the resulting solution was “parameter 6”. The Pd(OAc)₂ “parameter 7”, PPh₃ “parameter 8”, 2 M Na₂CO_(3(aq)) “parameter 9” and “parameter 10” mL H₂O were added and heated under the condition of “parameter 11”. Before the temperature of the solution was decreased, “parameter 12” mL H₂O was added, stirred in the air until reaching room temperature, diluted with “parameter 13” mL EtOAc, and extracted with “parameter 14” mL H₂O. The organic layer was washed with 5% NaHCO_(3(aq)), washed with brine, added in “parameter 15” mg Darco G-60, stirred for “parameter 16” minutes, added in MgSO₄ for drying, stirred for “parameter 17” minutes, filtered by the sintered glass funnel covered with about 1 cm of Celite and a thin layer of Florisil, concentrated for drying and purified by flash column chromatography (silica gel, “parameter 18”) to obtain “parameter 19.”

TABLE 1 The parameter table for the synthesis of compounds 29 and 31-40 29 31 32 33 34 35 1 2- C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ phenylboronic 2-(methylthio) 4-(methylthio) methoxyphenylboronic (100 mg, (150 mg, 0.41 acid (43 mg, phenylboronic phenylboronic acid (65 mg, 0.28 mmol) mmol) 0.35 mmol) acid (59 acid (125 mg, 0.43 mmol) mg, 0.35 0.74 mmol) mmol) 2 2.0 2.0 2.0 2.0 2.0 3.0 3 transparent — — — transparent transparent colorless light yellow colorless 4 C₁₈H₂₀BrNO₂ 3- 3,4,5- C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ (100 mg, methoxyphenylboronic trimethoxybenzeneboronic (100 mg, 0.28 (100 mg, 0.28 (150 mg, 0.41 0.28 mmol) acid (62 mg, acid (106 mmol) mmol) mmol) 0.41 mmol) mg, 0.50 mmol) 5 30 30 10 30 30 25 6 turbid dirt turbid beige turbid beige turbid beige turbid orange turbid white yellow white white white yellow 7 2.5 mg, 0.011 1.2 mg,  1.9 mg, 0.008 1.9 mg, 0.008 2.2 mg, 0.01 2.7 mg, 0.01 mmol 0.005 mmol mmol mmol mmol mmol 8 5.6 mg, 0.021 3.1 mg, 0.01 5.2 mg, 0.02 5.4 mg, 0.02  7.0 mg, 0.027  10 mg, 0.04 mmol mmol mmol mmol mmol mmol 9 0.18 mL, 0.18 mL, 0.27 mL, 0.50 0.18 mL, 0.34 0.17 mL, 0.34 0.25 mL, 0.49 0.34 mmol  0.34 mmol mmol mmol mmol mmol 10 0.2 0.2 0.3 0.2 0.2 0.3 11 120° C. for 20 120° C. for 10 120° C. for 10 120° C. for 10 140° C. for 20 140° C. for 20 minutes minutes minutes minutes minutes minutes 12 0.7 0.7 1.0 0.7 0.7 1.1 13 10 5 10 10 20 20 14 10 0 0 0 10 20 15 100 100 150 117 106 180 16 5 30 5 15 20 10 17 10 30 10 10 10 10 18 EA/n-hexane = EA/n-hexane = EA/n-hexane = EA/n-hexane = EA/n-hexane = EA/n-hexane = 1/1 1/1 1/1 1/3 1/2 1/2 19 orange light yellow light yellow light yellow oil orange oil orange oil yellow oil oil products oil products products (90 products (66 products (148 products (106 (97 mg, 0.23 (102 mg, 0.23 mg, 0.25 mg, 0.16 mg, 0.37 mg, 0.27 mmol, 83%) mmol, 55%) mmol, 89%) mmol, 58%) mmol, 89%) mmol, 97%) 36 37 38 39 40 1 3,4- 2- 2-nitrophenylboronic 2-chlorophenyl 2- (methylenedioxy) cyanophenylboronic acid boronic acid acetylphenylboronic benzene acid (74 mg, (124 mg, 0.74 (77 mg, 0.49 acid boronic 0.50 mmol) mmol) mmol) (80 mg, 0.49 acid (86 mg, mmol) 0.52 mmol) 2 3.0 3.0 3.0 3.0 3.0 3 transparent transparent transparent transparent turbid white light orange light yellow light yellow colorless 4 C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ (150 mg, (151 mg, (152 mg, 0.42 (150 mg, 0.41 (149 mg, 0.41 0.41 mmol) 0.42 mmol) mmol) mmol) mmol) 5 30 35 30 25 30 6 turbid beige turbid turbid light turbid beige turbid beige white white yellow white yellow 7 3.0 mg, 0.01 3.0 mg, 0.01  4 mg, 0.018 3.0 mg, 0.01  3.0 mg, 0.012 mmol mmol mmol mmol mmol 8  11 mg, 0.04   10 mg, 0.037 16 mg, 0.06  11 mg, 0.042  10 mg, 0.037 mmol mmol mmol mmol mmol 9 0.25 mL, 0.25 mL, 0.37 mL, 0.74 0.25 mL, 0.49 0.25 mL, 0.50 0.49 mmol 0.49 mmol mmol mmol mmol 10 0.3 0.3 0.3 0.3 0.3 11 140° C. for 20 140° C. for 20 120° C. for 20 140° C. for 20 140° C. for 20 minutes minutes minutes minutes minutes 12 1.1 1.1 1.1 1.1 1.1 13 20 20 20 20 20 14 20 20 20 20 20 15 197 195 176 160 150 16 10 10 10 10 10 17 10 10 10 10 10 18 EA/n-hexane = EA/n-hexane = EA/n-hexane = EA/n-hexane = EA/n-hexane = 1/3 1/3 1/2 1/2 1/2 19 white solid light yellow light yellow light yellow oil white solid products (134 oil products oil products products (105 products (40 mg, 0.33 (33 mg, 0.09 (20 mg, 0.05 mg, 0.27 mg, 0.10 mmol, 81%) mmol, 20%) mmol, 12%) mmol, 65%) mmol, 24%)

Compound 44: To a solution of C₁₈H₂₀BrNO₂ (100 mg, 0.28 mmol) in 2-propanol (1.5 mL) in a 10-mL thick walled Pyrex reaction vessel, 3,5-dimethoxybenzeneboronic acid (62 mg, 0.34 mmol) was added. After stirring for 30 min, Pd(OAc)₂ (2.2 mg, 0.01 mmol), PPh₃ (8.0 mg, 0.03 mmol), 2 M Na₂CO_(3(aq)) (0.17 mL, 0.34 mmol), and H₂O (0.7 mL) were added. Then the mixture was heated at 140° C. for 10 min in a microwave synthesizer, and H₂O (0.35 mL) was added before cooling to room temperature. The resulting solution was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with 5% NaHCO_(3(aq)) (10 mL) and brine. The organic solution was treated with Darco G-60 (100 mg) and stirred at room temperature for 30 min, and then dried over MgSO₄, filtered (the sintered glass funnel was charged with Celite to a depth of 1 cm and Florisil was spread evenly on the top of the Celite), and evaporated. The crude residue was chromatographed (silica gel, EtOAc/n-hexane=1/1) to afford a yellow oil (76 mg, 0.18 mmol, 65%).

Compound 45: To a solution of C₁₈H₂₀BrNO₂ (100 mg, 0.28 mmol) in 2-propanol (2.0 mL) in a 10-mL thick walled Pyrex reaction vessel, 2,3-dimethoxyphenylboronic acid (62 mg, 0.34 mmol) was added. After stirring for 30 min, Pd(OAc)₂ (2.0 mg, 0.009 mmol), PPh₃ (3.7 mg, 0.014 mmol), 2 M Na₂CO₃(aq) (0.18 mL, 0.36 mmol), and H₂O (0.2 mL) were added. Then the mixture was heated at 120° C. for 10 min in a microwave synthesizer, and H₂O (0.7 mL) was added before cooling to room temperature. The resulting solution was diluted with H₂O (5 mL) and extracted with EtOAc (5 mL). The organic layer was washed with 5% NaHCO_(3(aq)) (5 mL) and brine. The organic solution was treated with Darco G-60 (100 mg) and stirred at room temperature for 30 min, and then dried over MgSO₄, filtered (the sintered glass funnel was charged with Celite to a depth of 1 cm and Florisil was spread evenly on the top of the Celite), and evaporated. The crude residue was chromatographed (silica gel, EtOAc/n-hexane=1/1) to afford a yellow oil (82 mg, 0.20 mmol, 71%).

Compounds 15, 60, 85, 95-96, and 98: Table 2 is a parameter table. The starting material “parameter 1” was added into a reaction flask at room temperature under N₂, and “parameter 2” mL HOAc was added thereinto. The Pb(OAc)₄ “parameter 3” was added, and then the solution was “parameter 4”, poured into a conical flask and added with “parameter 5” mL Na₂CO₃ (sat) slowly. The pH of the aqueous layer was alkaline (pH=“parameter 6”). The solids produced in neutralization was filtered. The filter cake was washed with CH₂Cl₂. The filtrate was extracted with “parameter 7” mL CH₂Cl₂. The organic layer was washed with brine, added with MgSO₄ for drying, stirred for 5 minutes, filtered with the sintered glass funnel and concentrated for drying to obtain “parameter 8” product. The crude product was used in the following reaction without further purification.

The solution which was added in HBr “parameter 9” in the room temperature air and the appearance of the solution was “parameter 10.” After stirring for “parameter 11” hours, “parameter 12” mL Na₂CO₃ (sat) and “parameter 13” mL CH₂Cl₂ were added slowly to the solution. The pH of the aqueous layer was alkaline (pH=“parameter 14”), and then the “parameter 15” mL CH₂Cl₂ and “parameter 16” mL H₂O were added for extraction. The organic layer was washed with brine, added with MgSO₄ for drying, stirred for 5 minutes, filtered with the sintered glass funnel and concentrated for drying to obtain crude product “parameter 17” mg. The “parameter 19” was afforded after flash column chromatography (silica gel, “parameter 18”).

TABLE 2 The parameter table for the synthesis of compounds 15, 60, 85, 95-96, and 98 15 60 85 95 96 98 1 C₁₉H₂₂N₂O₄ C₁₈H₂₁NO₂ C₁₈H₂₀N₂O₄ C₁₈H₂₀ClNO₂ C₁₈H₂₀FNO₂ C₁₉H₂₂N₂O₄ (320 mg, (351 mg, (503 mg, 1.53 (1000 mg, (1002 mg, (285 mg, 0.93 mmol) 1.24 mmol) mmol) 3.15 mmol) 3.32 mmol) 0.83 mmol) 2 4.7 6.2 7.6 15.5 16.5 4.2 mL 3 636 mg, 1.43 830 mg, 1.87 1034 mg, 2.33 2101 mg, 2262 mg, 562 mg, 1.27 mmol mmol mmol 4.74 mmol 5.10 mmol mmol 4 red brown deep red transparent transparent tranparent transparent coffee color red coffee deep red burgundy red red brown color brown 5 25 40 60 100 130 25 6 8-9 8-9 8-9 8-9 8-9 8-9 7 40 50 80 100 130 40 8 deep orange deep orange red brown red brown red brown brown oil red solid red solid solid (498 mg, solid (1089 solid (1088 (263 mg, (303 mg, (282 mg, 1.29 mmol) mg, 2.91 mg, 3.04 0.66 mmol) 0.76 mmol) 0.83 mmol) mmol) mmol) 9 5 mL, 48% 6 mL, 48% 10 mL, 48% 15 mL, 48% 15 mL, 48% 5 mL, 48% wt wt wt wt wt wt 10 turbid orange turbid yellow turbid orange turbid orange turbid orange turbid orange 11 1 3 2 1.5 1.5 0.5 12 35 35 70 100 100 35 13 20 20 50 50 50 20 14 8-9 8-9 8-9 9-10 9-10 8-9 15 20 15 50 80 60 50 16 0 0 30 30 10 0 17 225 344 433 1013 973 195 18 MeOH/ EA/n-hexane = EA/n-hexane = MeOH/CH₂Cl₂ = EA/n-hexane = MeOH/CH₂Cl₂ = CH₂Cl₂ = 1/2 1/1 1/100 1/3 1/90 1/100 19 orange beige white yellow solid white solid white solid orange yellow oil solid products (363 products (747 products (752 yellow oil products products mg, 0.89 mg, 1.88 mg, 1.98 products (179 mg, (260 mg, mmol, 59%) mmol, 60%) mmol, 60%) (170 mg, 0.42 mmol, 0.72 mmol, 0.40 mmol, 46%) 58%) 49%)

Compounds 11-12, 63-67, 67-70, 74-75, and 78: Table 3 is a parameter table. The starting material “parameter 1” was added into a flask at room temperature under N₂, and then the “parameter 2” mL IPA and “parameter 3” were added thereinto. The starting material was dissolved at “parameter 4” ° C. The appearances of reaction solution were “parameter 5” and “parameter 7” in about “parameter 6” minutes, and then the solution was heated at 110˜120° C. for “parameter 8” hours and concentrated in room temperature. The “parameter 9” mL MeOH was added and the resulting mixture was stirred for “parameter 10” minutes. To the solution, which is “parameter 11” in a ice-bath, NaBH₄(s) “parameter 12” was added slowly under N₂ and stirred for “parameter 13” minutes. The solution, which is “parameter 14,” was added with “parameter 15” mL H₂O and extracted with “parameter 16” mL CHCl₃. The organic layer was added with MgSO₄ for drying, stirred for “parameter 17” minutes, filtered, and concentrated to obtain “parameter 18”. The “parameter 20” was afforded after flash column chromatography (silica gel, “parameter 19”).

TABLE 3 The parameter table for the synthesis of compounds 11-12, 63-67, 67-70, 74-75, and 78 11 12 63 64 65 66 1 C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ (20, 1000 (20, 300 (20, 300 (20, 300 mg, (20, 1001 mg, (20, 301 mg, mg, 5.64 mg, 1.69 mg, 1.69 1.69 mmol) 5.65 mmol) 1.70 mmol) mmol) mmol) mmol) 2 35 10 10 10 35 14 3 2- C₉H₁₀BrNO₂ C₈H₈NO₂Br C₈H₈NO₂Br C₈H₈NO₂Br 4- fluorophenethyl (1215 mg, (1127 mg, (866 mg, 3.76 (3810 mg, chlorophenethyl bromide 4.98 mmol) 4.89 mmol) mmol) 16.56 mmol) bromide (3438 mg, (1115 mg, 16.93 5.08 mmol) mmol) 4 80 88 60 75 — 80 5 transparent transparent transparent transparent — transparent orange white light light yellow — yellow yellow 6 — 210 30 10 — 120 7 — turbid turbid turbid transparent turbid yellow yellow yellow orange yellow yellow 8 18 19.5 18 16 17 24 9 35 15 15 15 35 15 10 10 10 10 10 10 10 11 transparent turbid turbid turbid yellow — transparent light yellow yellow yellow brown 12 836 mg, 266 mg, 264 mg, 206 mg, 3.39 853 mg, 22.53 576 mg, 15.2 22.1 mmol 7.03 mmol 6.97 mmol mmol mmol mmol 13 20 20 20 20 10 20 14 opaque transparent turbid turbid orange — opaque pinky brown yellow orange orange 15 100 30 30 0 0 30 16 100 30 30 30 100 30 17 5 5 5 5 5 5 18 light orange oil orange orange solid — orange solid orange products solid crude crude produts crude produts solid produts products 19 MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl = MeOH/CH₂Cl₂ = 1/90 1/90 1/60 1/60 1/80 1/90 20 white solid yellow oil canary white solid beige yellow white solid products products yellow products (541 solid products products (448 (1501 mg, (503 mg, solid mg, 1.65 (1558 mg, mg, 1.41 4.98 mmol, 1.47 mmol, products mmol, 97%) 4.74 mmol, mmol, 81%) 88%) 87%) (439 mg, 84%) 1.34 mmol, 79%) 67 69 70 74 75 78 1 C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ (20, 300 (20, 300 (20, 301 (20, 300 mg, (20, 1002 mg, (20, 300 mg, mg, 1.69 mg, 1.69 mg, 1.70 1.69 mmol) 5.64 mmol) 1.69 mmol) mmol) mmol) mmol) 2 10 10 10 10 35 10 3 C₈H₇BrCl₂ C₈H₈Br₂ C₁₀H₁₃O₂Br C₁₀H₁₃O₂Br 2- C₉H₁₀BrNO₂ (1.00 g, (1.00 g, (1.0 g, (1.0 g, 4.08 chlorophenethyl (989 mg, 4.05 3.94 3.79 mmol) 4.65 mmol) mmol) bromide mmol) mmol) (3716 mg, 16.93 mmol) 4 80 80 70 80 80 75 5 transparent transparent transparent transparent transparent transparent yellow yellow light orange yellow yellow white yellow 6 120 90 120 120 — 60 7 turbid turbid turbid turbid yellow — turbid yellow yellow yellow yellow 8 25 19 19 18 17 19.5 9 15 15 15 15 35 15 10 10 10 — — 10 10 11 transparent transparent transparent transparent turbid yellow turbid yellow yellow yellow yellow orange yellow 12 257 mg, 270 mg, 272 mg, 270 mg, 7.13 825 mg, 21.8 271 mg, 7.16 6.78 mmol 7.14 mmol 7.17 mmol mmol mmol mmol 13 20 20 20 20 20 20 14 opaque opaque transparent transparent opaque pinky transparent orange orange orange orange orange light orange 15 30 30 30 30 100 30 16 30 30 30 30 100 30 17 5 5 5 5 5 5 18 orange orange orange orange yellow light orange orange oil solid crude solid crude solid solid products solid products products produts produts products 19 MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = 1/100 1/100 1/100 1/60 1/90 1/90 20 yellow white solid white solid beige white solid yellow solid products products white products oil products (626 mg, (504 mg, solid products (1601 mg, products (492 (442 mg, 1.73 mmol, 1.61 mmol, (452 mg, 1.32 5.04 mmol, mg, 1.44 1.26 mmol, 102%) 95%) mmol, 78%) 89%) mmol, 85%) 74%)

Compound 68: A mixture of C₁₀N₁₁NO₂ (300 mg, 1.69 mmol), C₈H₈Br₂ (1.00 g, 3.79 mmol), and 2-propanol (10 mL) was heated to reflux for 23 h. The resulting solution was cooled to room temperature, and evaporated. The crude was dissolved in MeOH (15 mL), cooled to 0° C. in ice-bath, and then NaBH₄ (420 mg, 11.1 mmol) was added in portions under N2. The mixture was stirred for another 20 min and then concentrated. The residue was treated with CHCl₃ (30 mL) and H₂O (30 mL) and then the organic layer was dried over MgSO₄, filtered and evaporated. The purification was performed by the precipitation method. The crude product was dissolved with 5 mL of EtOAc, and then the product was precipitates with 10 mL of n-hexane to afford a beige solid (620 mg, 1.71 mmol).

Compound 121: To a solution of C₁₉H₂₃NO₂ (250 mg, 0.84 mmol) in HOAc (4.2 mL), Pb(OAc)₄ (579 mg, 1.31 mmol) was added and the mixture was stirred at room temperature under N₂ for 15 min. The reaction mixture was diluted with CH₂Cl₂ and Na₂CO₃ (sat) (20 mL) was added slowly. The solids formed in neutralization were removed by filtration and washed with CH₂Cl₂. The combined filtrate was extracted with CH₂Cl₂ (35 mL), and then the organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated to afford a brown oil (480 mg, 1.35 mmol), which was used in the following reaction without further purification. To a solution of the crude oil in CH₂Cl₂ (17 mL), 1,3-dimethoxybenzene (0.17 mL, 1.3 mmol) and trifluoroacetic acid (0.84 mL) were added. The resulting mixture was stirred at room temperature for 30 min, and then Na₂CO₃ (sat) (20 mL) was added slowly. The resulting solution was extracted with CH₂Cl₂ (18 mL) and then the organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated. The crude residue was chromatographed (silica gel, MeOH/CH₂Cl₂=1/10) to afford a red-brown oil (214 mg, 0.49 mmol, 59%).

Compounds 6, 105-110, 114-115, 120, 122, 123 and 125: Table 4 is a parameter table. The starting material “parameter 1” was added into a flask at room temperature under N₂ and dissolved with “parameter 2” mL HOAc. The solution which was “parameter 3” was added with Pb(OAc)₄ “parameter 4,” and then the resulting solution which was “parameter 5” was stirred for “parameter 6” minutes, poured into a 125 mL conical flask, stirred and added slowly with “parameter 7” mL Na₂CO₃(sat). The pH of the aqueous layer was alkaline (pH=8-9). The solid produced by neutralization was filtered and washed with CH₂Cl₂. The filtrate was extracted with “parameter 8” mL CH₂Cl₂. The organic layer was washed with brine, added with MgSO₄ for drying, stirred for 5 minutes, filtered, and concentrated to afford “parameter 9”. The crude product was used in the following reaction without further purification.

The crude product was dissolved in “parameter 10” mL CH₂Cl₂ at room temperature under N₂. The solution which was “parameter 11” was added with 1,3-dimethoxybenzene “parameter 12” and trifluoroacetic acid “parameter 13”. The color of the solution turned into “parameter 14”. After the solution was stirred for “parameter 15” minutes, “parameter 16” mL Na₂CO₃(sat) was added slowly. The pH of the aqueous layer was alkaline (pH=8-9), and “parameter 17” mL CH₂Cl₂ was added for extraction. The organic layer was washed with brine, added with MgSO₄ for drying, stirred for 5 minutes, filtered, and concentrated to obtain “parameter 18” mg crude product. The “parameter 20” was afforded after flash column chromatography (silica gel, “parameter 19”).

TABLE 4 The parameter table for the synthesis of compounds 6, 105-110, 114-115, 120, 122, 123 and 125 6 105 106 107 108 1 C₁₈H₂₀FNO₂ C₁₈H₂₀N₂O₄ C₁₈H₂₀ClNO₂ C₁₈H₁₉Cl₂NO₂ C₁₈H₂₀BrNO₂ (251 mg, (250 mg, (160 mg, 0.50 (250 mg, 0.71 (250 mg, 0.69 0.83 mmol) 0.76 mmol) mmol mmol) mmol) 2 4.2 3.8 2.5 3.6 3.5 3 light orange transparent transparent transparent light transparent light yellow light yellow light yellow green yellow 4 605 mg, 509 mg, 337 mg, 0.76 473 mg, 1.07 459 mg, 1.04 1.36 mmol 1.15 mmol mmol mmol mmol 5 translucent transparent deep coffee red black transparent red coffee red brown color coffee color color 6 15 15 60 27 15 7 25 25 20 25 40 8 35 40 40 50 9 red coffee red coffee coffee color oil red coffe color oil deep coffee color oil color oil products (218 products (291 mg, color oil products products mg, 0.58 0.71 mmol) products (214 (285 mg, (240 mg, mmol) mg, 0.51 mmol) 0.79 mmol) 0.62 mmol) 10 16 15 12 14 10 11 transparent transparent transparent red transparent red transparent red red coffee deep red coffee color coffee color coffee color color brown 12 0.16 mL, 0.14 mL, 0.11 mL, 0.87 0.14 mL, 1.06 0.10 mL, 0.77 1.2 mmol 1.1 mmol mmol mmol mmol 13 0.79 mL 0.73 mL 0.58 mL 0.71 mL 0.51 mL 14 transparent transparent transparent red transparent red transparent red red coffee deep black coffee brown coffee brown to coffee brown to color to tea color to to transparent transparent light transparent light transparent transparent light coffee coffee color coffee color light coffee tea color color color 15 30 30 60 30 30 16 20 25 10 20 30 17 19 20 23 26 30 18 417 480 327 490 325 19 MeOH/ EA/n-hexane = MeO/CH₂Cl₂/ MeOH/CH₂Cl₂/ MeOH/CH₂Cl₂/ CH₂Cl₂/ 1/1 NH₄OH = NH₄OH = NH₄OH = NH₄OH = 1/100/0.1 1/100/0.1 1/100/0.1 1/100/0.1 20 light orange light orange coffee color oil coffee color oil red coffee color yellow solid yellow solid products (130 products (152 mg, oil products (39 products products mg, 0.29 0.31 mmol, 44%) mg, 0.11 mmol, (126 mg, (151 mg, mmol, 57%) 11%) 0.29 mmol, 0.33 mmol, 35%) 43%) 109 110 114 115 120 1 C₁₈H₂₀BrNO₂ C₁₉H₂₃NO₃ C₁₉H₂₃NO₂ C₁₈H₂₀ClNO₂ (250 C₁₉H₂₃NO₃ (250 (250 mg, (250 mg, (250 mg, 0.73 mg, 0.79 mmol) mg, 0.798 mmol) 0.69 mmol) 0.80 mmol) mmol) 2 3.6 4 3.7 4 4 3 transparent transparent transparent transparent light light yellow light green light yellow light yellow orange yellow 4 470 mg, 569 mg, 505 mg, 1.14 570 mg, 1.29 532 mg, 1.20 1.06 mmol 1.28 mmol mmol mmol mmol 5 transparent transparent transparent red translucent red deep coffee color coffee color red coffee coffee color coffee color color 6 15 15 15 15 15 7 25 25 30 25 25 8 35 40 35 35 35 9 red coffee red coffee red coffee red coffee color red coffee color color oil color oil color oil oil products (300 oil products (290 products products products (253 mg, 0.80 mmol) mg, 0.781 mmol) (262 mg, (243 mg, mg, 0.63 0.62 mmol) 0.65 mmol) mmol) 10 13 13 13 16 16 11 transparent transparent coffee color transparent red transparent red red coffee red coffee coffee color coffee color color color 12 0.12 mL, 0.13 mL, 0.13 mL, 0.95 0.16 mL, 1.2 0.15 mL, 1.2 0.93 mmol 0.98 mmol mmol mmol mmol 13 0.62 mL 0.65 mL 0.63 mL 0.79 mL 0.78 mL 14 transparent transparent coffee color to transparent red transparent red red coffee red coffee light coffee coffee color to coffee color to brown to color to color transparent light transparent transparent transparent coffee color coffee color light coffee light coffee color color 15 70 30 30 30 30 16 15 20 20 25 25 17 27 22 22 19 19 18 342 450 433 480 560 19 EtOAc/n- EA/n-hexane = MeOH/CH₂Cl₂ = EA/n-hexane = MeOH/CH₂Cl₂/NH₄OH = hexane = 1/2 1/1 1/100 1/2 1/100/0.1 20 light brown light brown red coffee orange solid coffee color oil oil products oil products color oil products (128 mg, products (162 (80 mg, (217 mg, products (129 0.28 mmol, 36%) mg, 0.36 mmol, 0.18 mmol, 0.48 mmol, mg, 0.26 45%) 26%) 60%) mmol, 36%) 122 123 125 1 C₁₈H₂₀ClNO₂ C₁₉H₂₃NO₃ C₁₉H₂₃NO₂ (250 mg, (250 mg, (251 mg, 0.84 0.79 mmol) 0.80 mmol) mmol) 2 4.2 4 4.3 3 transparent transparent transparent orange orange light orange yellow yellow yellow 4 540 mg, 578 mg, 580 mg, 1.31 1.22 mmol) 1.30 mmol mmol 5 deep coffee deep coffee transparent red color color coffee color 6 17 15 15 7 25 25 35 8 35 35 35 9 red coffee deep red red coffee color oil coffee color color oil products oil products products (283 (286 mg, (290 mg, mg, 0.80 0.76 mmol) 0.78 mmol) mmol) 10 13 16 16 11 transparent transparent transparent red red coffee deep red coffee color color coffee color 12 0.15 mL, 0.15 mL, 0.16 mL, 1.2 1.1 mmol 1.2 mmol mmol 13 0.76 mL 0.78m 0.8 mL 14 transparent transparent transparent red coffee deep red deep red coffee color to coffee color color to transparent to deep transparent coffee color coffee color light coffee color 15 33 30 30 16 25 25 25 17 22 19 19 18 430 430 506 19 EA/n-hexane = EA/n-hexane = MeOH/CH₂Cl₂ = 1/1 1/1 1/200 20 orange light brown light orange yellow solid oil products yellow solid products (140 mg, products (135 (151 mg, 0.31 mmol, mg, 0.31 0.33 mmol, 39%) mmol, 37%) 42%)

Compounds 7 and 142: Table 5 is a parameter table. “Parameter 1” and 2-methoxyphenylboronic acid (46 mg, 0.30 mmol) were added into the reaction vessel for microwave-assisted heating and dissolved with 2-propanol (2 mL), and stirred for 30 minutes. Pd(OAc)₂ “parameter 2”, PPh₃ “parameter 3”, 2 M Na₂CO_(3(aq)) (0.14 mL, 0.28 mmol), and H₂O (0.2 mL) were added and the mixture was heated at 120° C. for 20 minutes using a microwave synthesizer. Before the temperature of the solution was decreased, the solution was added with H₂O (0.7 mL), stirred in the air until reaching room temperature, diluted with 10 mL of EtOAc, and extracted with 10 mL of H₂O. The organic layer was washed with 5% NaHCO_(3(aq)), washed with brine, added in “parameter 4” mg Darco G-60, stirred for 10 minutes, added in MgSO₄ for drying, stirred for 10 minutes, filtered by the sintered glass funnel covered with about 1 cm of Celite and a thin layer of Florisil, and concentrated. The crude product was purified by flash column chromatography (silica gel, “parameter 5”) to obtain a yellow oil “parameter 6.” Free base “parameter 7” was dissolved in CH₂Cl₂, and then a solution of HCl in CH₂Cl₂ was added until pH=1. The resulting mixture was concentrated to obtain hydrochloride salt “parameter 8”.

TABLE 5 The parameter table for the synthesis of compounds 7 and 142 7 142 1  103 mg, 0.24   104 mg, 0.25  mmol mmol 2 1.4 mg, 0.006 2.0 mg, 0.009 mmol mmol 3 6.5 mg, 0.024 5.9 mg, 0.022 mmol mmol 4 112 117 5 1/4 2/1 6 88 mg, 0.20 mmol, 76 mg, 0.17 mmol, 83% 72% 7 83 mg, 0.20 mmol 18 mg, 0.04 mmol 8 beige white solid light yellow oil products (100 mg, products (20 mg, 0.20 mmol) 0.04 mmol)

Compound 150: To a solution of C₁₈H₂₀BrNO₂ (100 mg, 0.28 mmol) in DMF (2 mL), trimethylphenyl-ammonium chloride ((CH₃)₃PhNCl, 102 mg, 0.59 mmol) and t-BuOK (67 mg, 0.60 mmol) were added. The suspension was heated to 60° C. under N₂ for 3.5 h, and then (CH₃)₃PhNCl (102 mg, 0.59 mmol) was added and heated to 70° C. for 4.5 h. After cooling to room temperature, the reaction mixture was treated with CHCl₃ (10 mL) and 5% NaOH_((aq)) (20 mL). The organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated. The crude residue was chromatographed (silica gel, EtOAc/n-hexane=1/4) to afford a yellow solid (83 mg, 0.22 mmol, 79%).

Compound 152: To a solution of C₁₈H₁₉BrN₂O₄ (406 mg, 1.00 mmol) in DMF (9 mL), which was cooled to 0° C. and degassed, NaH (40 mg, 1.67 mmol) and CH₃I (0.06 mL, 0.98 mmol) in DMF (1 mL) were added. After stirring for 10 min, NH₄Cl (111 mg, 2.08 mmol) was added, and then the reaction mixture was treated with diethyl ether (100 mL) and H₂O (100 mL). The organic layer was washed with brine, dried over MgSO₄, filtered and evaporated. The crude residue was chromatographed (silica gel, EtOAc/n-hexane=1/2) to afford a yellow solid (123 mg, 0.29 mmol, 30%).

Compound 153: To a solution of C₁₈H₁₉BrClNO₂ (300 mg, 0.75 mmol) in DMF (6 mL), (CH₃)₃PhNCl (542 mg, 3.16 mmol) and t-BuOK (333 mg, 2.97 mmol) were added. The suspension was heated to 60° C. under N₂ for 16 h, and then heated to 70° C. for 1 h. After cooling to room temperature, the reaction mixture was treated with Et₂O (100 mL) and H₂O (100 mL). The organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated. The crude residue was chromatographed (silica gel, EtOAc/n-hexane=1/4) to afford a white solid (189 mg, 0.46 mmol, 61%).

Compound 154: To a solution of C₁₈H₁₉BrFNO₂ (400 mg, 1.05 mmol) in DMF (8 mL), (CH₃)₃PhNCl (727 mg, 4.23 mmol) and t-BuOK (468 mg, 4.17 mmol) were added. The suspension was heated to 70° C. under N₂ for 16 h. After cooling to room temperature, the reaction mixture was treated with Et₂O (100 mL) and H₂O (100 mL). The organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated. The crude residue was chromatographed (silica gel, EtOAc/n-hexane=1/4) to afford a white solid (247 mg, 0.63 mmol, 60%).

Compounds 157-159, 165-168 and 171-173: Table 6 is a parameter table. “Parameter 1” was added into a reaction vessel for microwave-assisted heating and dissolved with “parameter 2” mL 2-propanol. “Parameter 3” was added thereinto, and stirred for 30 minutes. Pd(OAc)₂ “parameter 4”, PPh₃ “parameter 5”, 2 M Na₂CO_(3(aq))“parameter 6” and “parameter 7” mL H₂O were added and heated to 120° C. for 20 min using a microwave synthesizer. Before the temperature of the solution was decreased, “parameter 8” mL H₂O was added, and then cooled to room temperature, diluted with 10 mL EtOAc, and extracted with 10 mL H2O. The organic layer was washed with 5% NaHCO3(aq) followed by brine, added in “parameter 9” mg Darco G-60, stirred for 10 min, filtered by the sintered glass funnel covered with about 1 cm of Celite and a thin layer of Florisil, concentrated, and purified by flash column chromatography (silica gel, “parameter 10”) to obtain “parameter 11.”

TABLE 6 The parameter table for the synthesis of compounds 157-159, 165-168 and 171-173 157 158 159 165 166 1 2- 2- 2- 2-fluorophenyl 2-chlorophenyl fluorophenylboronic chlorophenylboronic methoxyphenylboronic boronic acid boronic acid acid (58 acid (55 mg, acid (55 mg, (55 mg, 0.39 (60 mg, 0.38 mg, 0.41 mmol) 0.35 mmol) 0.36 mmol) mmol) mmol) 2 2 1.8 1.8 2 2 3 C₁₉H₂₄BrNO₂ C₁₉H₂₄BrNO₂ C₁₉H₂₄BrNO₂ C₁₉H₂₁BrFNO₂ C₁₉H₂₁BrFNO₂ (102 mg, 0.27 (90 mg, 0.24 (89 mg, 0.24 (105 mg, 0.27 (101 mg, 0.26 mmol) mmol) mmol) mmol) mmol) 4 1.5 mg, 0.007 1.6 mg, 0.007 1.7 mg, 0.0076 1.6 mg, 0.007 1.4 mg, 0.006 mmol mmol mmol mmol mmol 5 4.2 mg, 0.016 8.0 mg, 0.03 4.7 mg, 0.018 6.0 mg, 0.023 5.6 mg, 0.021 mmol mmol mmol mmol mmol 6 0.20 mL, 0.40 0.18 mL, 0.36 0.18 mL, 0.36 0.19 mL, 0.38 0.19 mL, 0.38 mmol mmol mmol mmol mmol 7 0.2 0.18 0.18 0.2 0.2 8 0.7 0.63 0.63 0.7 0.7 9 117 113 99 101 117 10 1/3 1/3 1/2 1/4 1/4 11 beige yellow oil light yellow oil light yellow oil yellow oil light yellow oil products (103 products (58 products (69 products (108 products (50 mg, 0.26 mmol, mg, 0.14 mmol, mg, 0.17 mmol, mg, 0.26 mmol, mg, 0.12 mmol, 97%) 59%) 71%) 99%) 47%) 12 C₂₅H₂₆FNO₂ C₂₅H₂₆ClNO₂ C₂₆H₂₉NO₃ (69 C₂₅H₂₅F₂NO₂ C₂₅H₂₅ClFNO₂ (103 mg, 0.26 (31 mg, 0.08 mg, 0.17 mmol) (108 mg, 0.26 (50 mg, 0.12 mmol) mmol) mmol) mmol) 13 white solid light yellow light yellow light yellow beige white products (113 solid products solid products solid products solid muriate mg, 0.26 mmol) (36 mg, 0.08 (66 mg, 0.15 (116 mg, 0.26 products (55 mmol) mmol) mmol) mg, 0.12 mmol) 167 168 171 172 173 1 2- 2- 2- 2-chlorophenyl 2- fluorophenylboronic chlorophenylboronic fluorophenylboronic boronic acid methoxyphenylboronic acid (45 acid (48 acid (50 (56 mg, 0.36 acid (56 mg, 0.37 mg, 0.32 mmol) mg, 0.31 mmol) mg, 0.36 mmol) mmol) mmol) 2 1.8 1.7 2 2 2 3 C₁₉H₂₁BrClNO₂ C₁₉H₂₁BrClNO₂ C₁₉H₂₂BrN₂O₄ C₁₉H₂₂BrN₂O₄ C₁₉H₂₂BrN₂O₄ (90 mg, 0.22 (84 mg, 0.20 (98 mg, 0.23 (100 mg, 0.24 (101 mg, 0.24 mmol) mmol) mmol mmol) mmol) 4 2.0 mg, 0.009 1.0 mg, 0.004 1.7 mg, 0.0076 1.8 mg, 0.0072 1.8 mg, 0.008 mmol mmol) mmol mmol mmol 5 4.7 mg, 0.02 4.4 mg, 0.02 5.7 mg, 0.022 6.0 mg, 0.023 6.5 mg, 0.025 mmol mmol mmol mmol mmol 6 0.19 mL, 0.38 0.16 mL, 0.32 0.18 mL, 0.36 0.18 mL, 0.36 0.18 mL, 0.36 mmol mmol mmol mmol mmol 7 0.2 0.17 0.2 0.2 0.2 8 0.7 0.6 0.7 0.7 0.7 9 105 90 112 101 115 10 1/3 1/3 1/1 1/2 1/1 11 yellow oil beige yellow beige solid beige white beige yellow products (91 solid products products (75 solid products solid products mg, 0.21 mmol, (66 mg, 0.15 mg, 0.17 mmol, (72 mg, 0.16 (88 mg, 0.20 97%) mmol, 73%) 71%) mmol, 66%) mmol, 81%) 12 C₂₅H₂₅ClFNO₂ C₂₅H₂₅Cl₂NO₂ C₂₅H₂₅FN₂O₄ C₂₅H₂₅ClN₂O₄ C₂₆H₂₈N₂O₅ (72 (91 mg, 0.21 (66 mg, 0.15 (56 mg, 0.13 (72 mg, 0.16 mg, 0.16 mmol) mmol) mmol) mmol) mmol) 13 light yellow beige solid beige white beige yellow beige white solid products products (72 solid products solid products solid products (94 mg, 0.20 mg, 0.15 mmol) (61 mg, 0.13 (81 mg, 0.17 (80 mg, 0.16 mmol) mmol) mmol) mmol)

TABLE 7 The analytical data of the compounds in this invention Compound 7 number Name 6-Methoxy-8-(2-methoxyphenyl)-2-(3-(4-nitrophenyl) propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 1.69-1.90 (m, 2H), 2.29-2.45 (m, 2H), 2.60-2.78 (200 MHz, (m, 4H), 2.83-2.96 (m. 2H), 3.11 (d, J = 15.2 Hz, 1H), CDCl₃) 3.19 (d, J = 15.2 Hz, 1H), 3.75 (s, 3H), 3.88 (s, 3H), 5.37 (bs, 1H), 6.64 (s, 1H), 6.96-7.09 (m, 2H), 7.14 (dd, J = 7.3, 1.9 Hz, 1H), 7.22-7.32 (m, 2H), 7.32-7.43 (m, 1H), 8.05-8.16 (m, 2H) ¹³C NMR 28.4, 29.4, 33.5, 50.6, 54.2, 55.8, 56.0, 57.0, 110.3,  (50 MHz, 111.4, 121.0, 122.7, 123.7, 124.2, 125.2, 126.2, 129.3, CDCl₃) 131.6, 141.2, 145.2, 146.4, 150.4, 157.1 ESI-MS m/z 449 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₉N₂O₅ [M + H]⁺, 449.2076; found, 449.2087 Compound 8 number Name 6-Methoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-4-yl) propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 1.66-1.87 (m, 2H), 2.29-2.44 (m, 2H), 2.51-2.73 (200 MHz, (m, 4H), 2.89 (t, J = 5.8 Hz, 2H), 3.15 (dd, J = 17.1, CDCl₃) 15.3 Hz, 2H), 3.74 (s, 3H), 3.87 (s, 3H), 5.47 (s, 1H), 6.63 (s, 1H), 6.94-7.09 (m, 4H), 7.14 (dd, J = 7.4, 2.0 Hz, 1H), 7.30-7.44 (m, 1H), 8.44 (dd, J = 4.4, 1.6 Hz, 2H) 13C NMR 27.7, 29.3, 32.9, 50.6, 54.2, 55.8, 56.0, 57.1,  (50 MHz, 110.3, 111.4, 120.9, 122.8, 124.0, 124.2, 125.2, 126.3, CDCl₃) 129.4, 131.6, 141.2, 145.3, 149.7, 151.4, 157.1 ESIHRMS calcd for C₂₅H₂₉N₂O₃ [M + H]⁺, 405.2178; found, 405.2170 Compound 9 number Name 6-Methoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-3-yl) propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 1.65-1.87 (m, 2H), 2.30-2.46 (m, 2H), 2.50-2.75 (200 MHz, (m, 4H), 2.89 (t, J = 5.7 Hz, 2H), 3.16 (s, 2H), 3.74 (s, CDCl₃) 3H), 3.78 (s, 3H), 6.63 (s, 1H), 6.91-7.09 (m, 2H), 7.09-7.22 (m, 2H), 7.29-7.49 (m, 2H), 8.32-8.46 (m, 2H) ¹³C NMR 28.5, 29.3, 30.7, 50.6, 54.2, 55.7, 56.0, 57.2,  (50 MHz, 110.3, 111.4, 120.9, 122.8, 123.4, 124.2, 125.2, 126.3, CDCl₃) 129.4, 131.6, 135.9, 137.5, 141.2, 145.3, 147.3, 150.0, 157.1 ESIHRMS calcd for C₂₅H₂₉N₂O₃ [M + H]⁺, 405.2178; found, 405.2170 Compound 10 number Name 6,7-dimethoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-4- yl)propyl)-1,2,3,4-tetrahydroisoquinoline ¹H NMR 1.74-1.80 (m, 2H), 2.37 (t, J = 7.3 Hz, 2H), 2.59 (200 MHz, (t, J = 7.7 Hz, 2H), 2.63-2.72 (m, 2H), 2.92 (t, J = 5.8 CDCl₃) Hz, 2H), 3.12 (q, J = 14.8, 2H), 3.52 (s, 3H), 3.73 (s, 3H), 3.85 (s, 3H), 6.69 (s, 1H), 7.00 (q, J = 8.5 Hz, 2H), 7.06 (d, J = 5.8 Hz, 2H), 7.09 (dd, J = 7.4, 1.8 Hz, 2H), 7.36 (dt, J = 7.8, 1.8 Hz, 1H), 8.45 (d, J = 5.7, 2H) ¹³C NMR 27.7, 29.5, 32.8, 50.3, 54.1, 55.5, 55.8, 57.0, 60.6,  (50 MHz, 110.8, 111.8, 120.5, 124.0 (2C), 125.2, 126.2, 128.9, CDCl₃) 129.6 (2C), 131.1, 145.0, 149.7 (2C), 150.9, 151.3, 156.9 ESIHRMS calcd for C₂₆H₃₁N₂O₃ [M + H]⁺, 419.2335; found, 419.2317 Compound 11 number Name 2-(2-Fluorophenethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.68-2.89 (m, 6H), 2.89-3.01 (m, 2H), 3.61 (s, 2H), (200 MHz, 3.83 (s, 3H), 6.56 (s, 2H), 6.94-7.11 (m, 2H), 7.12-7.30 CDCl₃) (m, 2H) ¹³C NMR 27.2, 28.8, 51.1, 55.5, 56.0, 58.6, 110.8, 112.5,  (50 MHz, 115.4 (J = 22.1 Hz), 124.1 (J = 3.1 Hz), 125.5, 127.2 CDCl₃) (J = 15.9 Hz), 127.3, 127.9 (J = 7.9 Hz), 131.1 (J = 4.8 Hz), 143.8, 145.4, 161.3 (J = 243 Hz) ESI-MS m/z 302 ([M + H]⁺) EIHR-MS calcd for C₁₈H₂₁FNO₂ [M + H]⁺, 302.1556; found, 302.1554 Compound 12 number Name 6-Methoxy-2-(3-(4-nitrophenyl)propyl)-1,2,3,4-tetrahy droisoquinolin-7-ol ¹H NMR 1.84-2.05 (m, 2H), 2.44-2.56 (m, 2H), 2.63-2.74 (200 MHz, (m, 2H), 2.74-2.88 (m, 4H), 3.50 (s, 2H), 3.83 (s, 3H), CDCl₃) 6.54 (s, 1H), 6.56 (s, 1H), 7.30-7.42 (m, 2H), 8.09-8.20 (m, 2H) ¹³C NMR 28.4, 28.8, 33.6, 51.2, 55.6, 56.0, 57.3, 110.8, 112.4,  (50 MHz, 123.7, 125.5, 127.2, 129.4, 143.8, 145.4, 146.4, 150.3 CDCl₃) EIHR-MS calcd for C₁₉H₂₃N₂O₄ [M + H]⁺, 343.1658; found, 343.1661 Compound 15 number Name 8-Bromo-6-methoxy-2-(3-(4-nitrophenyl)propyl)- 1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 1.87-2.06 (m, 2H), 2.49-2.74 (m, 4H), 2.74-2.90 (200 MHz, (m, 4H), 3.53 (s, 2H), 3.85 (s, 3H), 6.57 (s, 1H), CDCl₃) 7.31-7.43 (m, 2H), 8.07-8.21 (m, 2H) ¹³C NMR 28.4, 29.3, 33.6, 50.4, 56.2, 56.4, 57.2, 109.0,  (50 MHz, 110.1, 123.8, 126.4, 127.2, 129.4, 141.3, 145.6, CDCl₃) 146.4, 150.2 ESI-MS m/z 421 ([M + H]⁺) EIHR-MS calcd for C₁₉H₂₂BrN₂O₄ [M + H]⁺, 421.0763; found, 421.0757 Compound 21 number Name 6-Methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹H NMR 2.71-2.96 (m, 8H), 3.61 (s, 2H), 3.84 (s, 3H), 6.57 (200 MHz, (s, 2H), 7.16-7.34 (m, 5H) CDCl₃) ¹³C NMR 28.8, 34.1, 51.2, 55.6, 56.0, 60.4, 110.8, 112.4,  (50 MHz, 125.5, 126.2, 127.3, 128.5, 128.9, 140.5, 143.8, 145.4 CDCl₃) Compound 29 number Name 6-Methoxy-8-(2-methoxyphenyl)-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.57-2.66 (m, 2H), 2.72-2.81 (m, 4H), 2.85-2.92 (200 MHz, (m, 2H), 3.25 (s, 2H), 3.74 (s, 3H), 3.86 (s, 3H), 6.63 CDCl₃) (s, 1H), 6.97-7.06(m, 2H), 7.11-7.28(m, 6H), 7.32-7.40 (m, 1H) ¹³C NMR 29.2, 34.0, 50.5, 54.2, 55.7, 56.0, 60.0, 110.2, 111.3,  (50 MHz, 120.9, 122.8, 124.1, 125.2, 126.0, 126.2, 128.4, 128.7, CDCl₃) 129.3, 131.6, 140.5, 141.1, 145.2, 157.1 ESI-MS m/z 390 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₈NO₃ [M + H]⁺, 390.2069; found, 390.2054 Compound 30 number Name 6-Methoxy-8-(4-methoxyphenyl)-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.59-2.68 (m, 2H), 2.73-2.82 (m, 4H), 2.92, (t, J = (200 MHz, 5.8 Hz, 2H), 3.29 (s, 2H), 3.83 (s, 3H), 3.87 (s, 3H), CDCl₃) 6.62 (s, 1H), 6.93-6.94, (m, 1H), 6.98-6.99 (m, 1H), 7.12-7.24 (m, 7H) ¹³C NMR 29.4, 34.0, 50.6, 55.0, 55.3, 56.1, 60.2, 110.0,  (50 MHz, 114.1, 125.4, 125.9, 126.0, 127.6, 128.4, 128.7, 130.9, CDCl₃) 140.4, 141.2, 145.4, 158.9 ESI-MS m/z 390 ([M + H]⁺), 412 ([M + Na]⁺) EIHR-MS calcd for C₂₅H₂₈NO₃ [M + H]⁺, 390.2069; found, 390.2067 Compound 31 number Name 6-Methoxy-8-(3-methoxyphenyl)-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.59-2.68 (m, 2H), 2.74-2.80 (m, 4H), 2.89-2.95 (200 MHz, (m, 2H), 3.31 (s, 2H), 3.78 (s, 3H), 3.86 (s, 3H), 6.63 CDCl₃) (s, 1H), 6.78-6.83, (m, 2H), 6.86-6.94 (m, 1H), 7.11-7.24 (m, 5H), 7.30-7.40 (m. 1H) ¹³C NMR 29.2, 33.8, 50.4, 54.7, 55.2, 56.0, 60.0, 110.1, 113.3,  (50 MHz, 115.2, 122.1, 125.3, 125.4, 126.1, 126.2, 128.4, 128.7, CDCl₃) 129.6, 136.9, 140.3, 141.0, 145.4, 159.7 ESI-MS m/z 390.2 ([M + H]⁺), 412.2 ([M + Na]⁺) EIHR-MS calcd for C₂₅H₂₈NO₃ [M + H]⁺, 390.2069; found, 390.2064 Compound 32 number Name 6-Methoxy-8-(3,4,5-trimethoxyphenyl)-2-phenethyl- 1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.62-2.71 (m, 2H), 2.78-2.85 (m, 4H), 2.91-2.96 (200 MHz, (m, 2H), 3.32 (s, 2H), 3.90 (s, 6H), 3.91 (s, 3H), 3.92 CDCl₃) (s, 3H), 5.41 (s, 1H), 6.46 (s, 2H), 6.65 (s, 1H), 7.13-7.30 (m, 5H) ¹³C NMR 29.5, 34.1, 50.5, 54.5, 56.2, 60.3, 61.0, 106.6,  (50 MHz, 110.3, 125.7, 126.2, 126.3, 128.5, 128.8, 131.0, 137.1, CDCl₃) 140.3, 140.9, 145.4, 153.5 ESI-MS m/z 449 ([M]⁺) EIHR-MS calcd for C₂₇H₃₂NO₅ [M + H]⁺, 450.2280; found, 450.2268 Compound 33 number Name 6-Methoxy-2-phenethyl-8-phenyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.57-2.66 (m, 2H), 2.72-2.79 (m, 4H), 2.89-2.94 (200 MHz, (m, 2H), 3.28 (s, 2H), 3.85 (s, 3H), 6.63 (s, 1H), CDCl₃) 7.10-7.14 (m, 2H), 7.19-7.25 (m, 5H), 7.32-7.48 (m, 3H) ¹³C NMR 29.3, 33.9, 50.5, 54.9, 56.1, 60.1, 110.1, 125.4,  (50 MHz, 126.1, 126.4, 127.5, 128.4, 128.6, 128.7, 129.8, 135.7, CDCl₃) 140.3, 141.0, 145.4 ESI-MS m/z 360 ([M + H]⁺) EIHR-MS calcd for C₂₄H₂₆NO₂ [M + H]⁺, 360.1964; found, 360.1956 Compound 34 number Name 6-Methoxy-8-(2-methylthiophenyl)-2-phenethyl- 1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.37 (s, 3H), 2.57-2.66 (m, 2H), 2.72-2.81 (m, 4H), (200 MHz, 2.89-2.92 (m, 2H), 3.22 (s, 2H), 3.88 (s, 3H), 6.67 (s, CDCl₃) 1H), 7.12-7.22 (m, 8H), 7.25-7.29 (m, 1H) ¹³C NMR 15.2, 29.2, 34.0, 50.5, 53.8, 56.0, 60.0, 110.6,  (50 MHz, 124.1, 124.7, 125.0, 125.6, 125.9, 126.1, 128.4, 128.6, CDCl₃) 128.8, 130.1, 133.9, 138.6, 140.5, 141.0, 145.2 ESI-MS m/z 406 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₈NO₂S [M + H]⁺, 406.1841; found, 406.1836 Compound 35 number Name 6-Methoxy-8-(4-methylthiophenyl)-2-phenethyl- 1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.51 (s, 3H), 2.63-2.68 (m, 2H), 2.74-2.81 (m, 4H), (200 MHz, 2.89-2.95 (m, 2H), 3.29 (s, 2H), 3.88 (s, 3H), 6.63 (s, CDCl₃) 1H), 7.14-7.21 (m, 6H), 7.25-7.33 (m, 3H) ¹³C NMR 15.7, 29.4, 33.9, 50.5, 55.0, 56.1, 60.2, 110.1,  (50 MHz, 125.5, 125.6, 126.1, 126.5, 128.4, 128.8, 130.3, 137.6, CDCl₃) 140.4, 141.1, 145.4 ESI-MS 406 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₈NO₂S [M + H]⁺, 406.1841; found, 406.1839 Compound 36 number Name 8-(Benzo[1,3]dioxo1-5-yl)-6-methoxy-2-phenethyl- 1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.61-2.70 (m, 2H), 2.73-2.84 (m, 4H), 2.89-2.94 (200 MHz, (m, 2H), 3.30 (s, 2H), 3.88 (s, 3H), 5.43 (bs, 1H), 6.00 CDCl₃) (bs, 2H), 6.63 (s, 1H), 6.68-6.73 (m, 2H), 6.86-6.90 (m, 1H), 7.16-7.26 (m, 5H) ¹³C NMR 29.5, 34.1, 50.6, 55.0, 56.2, 60.3, 101.2, 108.7,  (50 MHz, 110.1, 110.4, 123.1, 125.5, 125.9, 126.1, 128.5, 128.8, CDCl₃) 129.0, 140.4, 141.2, 145.3, 147.0, 147.8 ESI-MS m/z 404 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₆NO₄ [M + H]⁺, 404.1862; found, 404.1849 Compound 37 number Name 8-(2-Cyanophenyl)-6methoxy-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.61-2.80 (m, 6H), 2.87-2.94 (m, 2H), 3.12 (d, J = (200 MHz, 14.8 Hz, 1H), 3.32 (d, J = 14.9 Hz, 1H), 3.90 (s, 3H), CDCl₃) 6.68 (s, 1H), 7.12-7.29 (m, 5H), 7.35 (ddd, J = 7.7, 1.3, 0.6 Hz, 1H), 7.46 (td, J = 7.6, 1.3 Hz, 1H), 7.65 (td, J = 7.6, 1.5 Hz, 1H), 7.77 (ddd, J = 7.7, 1.4, 0.5 Hz, 1H) ¹³C NMR 29.2, 34.0, 50.3, 54.3, 56.1, 60.0, 111.2, 114.0,  (50 MHz, 118.2, 122.2, 125.1, 126.0, 126.2, 128.1, 128.5, 128.8, CDCl₃) 131.0, 132.8, 133.2, 140.3, 141.3, 145.3 ESI-MS m/z 385 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₅N₂O₂ [M + H]⁺, 385.1916; found, 385.1910 Compound 38 number Name 6-Methoxy-8-(2-nitrophenyl)-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.63-2.82 (m, 6H), 2.87-2.91 (m. 2H), 3.14 (d ,J = (200 MHz, 15.0 Hz, 1H), 3.40 (d, J = 14.9 Hz, 1H), 3.87 (s, 3H), CDCl₃) 6.65 (s, 1H), 7.12-7.26 (m, 5H), 7.30-7.36 (m, 1H), 7.48-7.58 (m, 1H), 7.60-7.70 (m, 1H), 8.01-8.08 (m, 1H) ¹³C NMR 28.9, 33.9, 50.3, 54.0, 56.1, 59.7, 110.6, 121.9,  (50 MHz, 124.6, 124.8, 125.8, 126.2, 128.5, 128.8, 131.0, 132.6, CDCl₃) 133.1, 140.3, 140.7, 145.0, 149.6 ESI-MS m/z 405 ([M + H]⁺) EIHR-MS calcd for C₂₄H₂₅N₂O₄ [M + H]⁺, 405.1814; found, 405.1800 Compound 39 number Name 8-(2-Chlorophenyl)-6-methoxy-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.59-2.69 (m, 2H), 2.72-2.82 (m, 4H), 2.88-2.91 (200 MHz, (m, 2H), 3.21 (d, J = 3.7 Hz, 2H), 3.85 (s, 3H), 6.65 (s, CDCl₃) 1H), 7.11-7.22 (m, 6H), 7.28-7.33 (m 2H), 7.43-7.52 (m, 1H) ¹³C NMR 29.1, 33.9, 50.4, 53.9, 56.0, 59.9, 110.5, 123.6,  (50 MHz, 125.4, 125.6, 126.0, 127.0, 128.4, 128.7, 129.1, 129.7, CDCl₃) 131.5, 134.1, 134.9, 140.4, 141.1, 145.2 ESI-MS m/z 394 ([M + H]⁺) EIHR-MS calcd for C₂₄H₂₅ClNO₂ [M + H]⁺, 394.1574; found, 394.1571 Compound 40 number Name 8-(2-Acetylphenyl)-6methoxy-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.15 (s, 3H), 2.53-3.00 (m. 8H), 3.05 (d, J = 15.4 (200 MHz, Hz, 1H), 3.28 (d, J = 15.1 Hz, 1H), 3.87 (s, 3H), 5.59 CDCl₃) (bs, 1H), 6.65 (s, 1H), 7.06-7.61 (m, 8H), 7.76 (dd, J = 7.5, 1.6 Hz, 1H) ESI-MS m/z 402 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₈NO₃ [M + H]⁺, 402.2069; found, 402.2061 Compound 41 number Name 8-(2-Fluorophenyl)-6-methoxy-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.61-2.68 (m, 2H), 2.72-2.84 (m, 4H), 2.88-2.92 (200 MHz, (m, 2H), 3.23 (d, J = 15.0 Hz, 1H), 3.37 (d, J = 15.0 CDCl₃) Hz, 1H), 3.89 (s, 3H), 5.52 (s, 1H), 6.67 (s, 1H), 7.12-7.35 (m, 9H) ¹³C NMR 29.3, 34.0, 50.5, 54.3, 56.1, 60.1, 110.7, 115.9 (d, J =  (50 MHz, 22.3 Hz), 119.7, 123.1 (d, J = 17.7 Hz), 124.2, 125.6, CDCl₃) 126.1, 128.4, 128.8, 129.7 (d, J = 7.9 Hz), 132.0, 140.1, 141.5, 145.2, 160.1 (d, J = 244 Hz) ESI-MS m/z 378.2 ([M + H]⁺) Compound 42 number Name (2-Methylphenyl)-6-methoxy-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.09 (s, 3H), 2.57-2.65 (m, 2H), 2.71-2.81 (m, 4H), (200 MHz, 2.90-2.92 (m, 2H), 3.02 (d, J = 15.3 Hz, 1H), 3.25 (d, CDCl₃) J = 15.2 Hz, 1H), 3.89 (s, 3H), 5.33 (s, 1H), 6.64 (s, 1H), 7.09-7.31 (m, 9H) ¹³C NMR 19.7, 29.4, 33.9, 50.6, 54.6, 56.1, 60.2, 110.0,  (50 MHz, 125.5, 125.6, 126.1, 128.0, 128.4, 128.8, 129.8, 130.3, CDCl₃) 135.0, 137.0, 140.4, 140.7, 145.3 ESI-MS m/z 374.2 ([M + H]⁺) Compound 43 number Name 8-(2-Isopropylphenyl)-6-methoxy-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 1.12-1.17 (m, 3H), 1.26-1.30 (m, 3H), 2.65-2.94 (200 MHz, (m, 8H), 3.12-3.20 (m, 2H), 3.63-3.65 (m, 1H), 3.91 (s, CDCl₃) 3H), 5.30 (s, 1H), 6.67 (s, 1H), 7.06-7.42 (m, 9H) ¹³C NMR 24.0, 24.5, 29.3, 30.3, 33.9, 50.7, 54.7, 56.0, 60.2,  (50 MHz, 110.0, 125.5, 125.8, 126.1, 128.4, 128.7, 128.9, 129.9, CDCl₃) 133.5, 140.3, 141.0, 145.2, 147.7 ESI-MS m/z 402.2 ([M + H]⁺) Compound 44 number Name 8-(3,5-Dimethoxyphenyl)-6-methoxy-2-phenethyl- 1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.58-2.72 (m, 2H), 2.73-2.82 (m, 4H), 2.93 (t, J = (200 MHz, 3.0 Hz, 2H), 3.33 (s, 2H), 3.79 (s, 6H), 3.90 (s, 3H), CDCl₃) 5.36 (s, 1H), 6.40 (s, 1H), 6.41 (s, 1H), 6.64 (s, 1H), 6.46-6.50 (m, 1H), 7.11-7.23 (m, 4H), 7.27-7.32 (m, 1H) ¹³C NMR 29.5, 34.1, 50.6, 54.8, 55.5, 56.2, 60.2, 100.0,  (50 MHz, 107.6, 110.3, 125.6, 126.1, 126.3, 128.5, 128.8, 137.5, CDCl₃) 140.4, 140.8, 145.4, 161.0 ESI-MS m/z 420 ([M + H]⁺) EIHR-MS calcd for C₂₆H₃₀NO₄ [M + H]⁺, 420.2175; found, 420.2167 Compound 45 number Name 8-(2,3-Dimethoxyphenyl)-6-methoxy-2-phenethyl- 1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.54-2.86 (m, 6H), 2.87-3.00 (m, 2H), 3.28 (s, 2H), (200 MHz, 3.62 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 5.46 (s, 1H), CDCl₃) 6.65 (s, 1H), 6.73 (dd, J = 7.6, 1.5 Hz, 1H), 6.95 (dd, J = 8.2, 1.4 Hz, 1H), 7.07-7.29 (m, 6H) ¹³C NMR 29.3, 33.9, 50.6, 54.2, 55.8, 56.0, 60.0, 60.8, 110.2,  (50 MHz, 112.0, 122.6, 123.1, 124.3, 125.3, 126.0, 126.2, 128.4, CDCl₃) 128.8, 129.7, 140.5, 140.9, 145.1, 147.0, 153.1 ESI-MS m/z 420 ([M + H]⁺) EIHR-MS calcd for C₂₆H₃₀NO₄ [M + H]⁺, 420.2175; found, 420.2159 Compound 60 number Name 8-Bromo-6-methoxy-2-phenethyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.70-3.01 (m, 8H), 3.64 (s, 2H), 3.86 (s, 3H), 6.58 (200 MHz, (s, 1H), 7.17-7.37 (m, 5H) CDCl₃) ¹³C NMR 29.3, 34.0, 50.4, 56.2, 56.4, 60.2, 109.0, 110.1,  (50 MHz, 126.2, 126.5, 127.3, 128.6, 128.9, 140.3, 141.2, 145.6 CDCl₃) ESI-MS calcd for C₁₈H₂₁BrNO₂ m/z 362.1 EIHR-MS calcd for C₁₈H₂₁BrNO₂ [M + H]⁺, 362.0755; found, 362.0782 Compound 61 number Name 6-Methoxy-2-(2-(1-naphthyl)ethyl)-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.68-2.97 (m, 6H), 3.23-3.47 (m, 2H), 3.68 (s, 2H), (200 MHz, 3.83 (s, 3H), 6.58 (s, 1H), 6.60 (s, 1H), 7.28-7.58 (m, CDCl₃) 4H), 7.64-7.91 (m, 2H), 8.00-8.17 (m, 1H) ¹³C NMR 28.8, 31.1, 51.3, 55.6, 56.0, 59.4, 110.8, 112.6,  (50 MHz, 123.9, 125.4, 125.6, 125.7, 126.1, 126.7, 127.0, 127.1, CDCl₃) 128.9, 132.0, 134.0, 136.5, 144.0, 145.6 EIHR-MS calcd for C₂₂H₂₃NO₂ [M]⁺, 333.1729; found, 333.1721 Compound 62 number Name 2-(2-(3-indolyl)ethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.76-2.94 (m, 6H), 3.00-3.15 (m, 2H), 3.66 (s, 2H), (200 MHz, 3.85 (s, 3H), 6.59 (s, 1H), 6.61 (s, 1H), 7.02-7.24 (m, CDCl₃) 3H), 7.32-7.40 (m, 1H), 7.61-7.69 (m, 1H), 8.03 (s, 1H) ¹³C NMR 23.2, 28.7, 51.1, 55.5, 55.9, 58.9, 110.7, 111.1,  (50 MHz, 112.3, 114.4, 118.8, 119.2, 121.5, 121.9, 125.5, 127.3, CDCl₃) 127.5, 136.2, 143.7, 145.3 EIHR-MS calcd for C₂₀H₂₂N₂O₂ [M]⁺, 322.1681; found, 322.1675 Compound 63 number Name 6-Methoxy-2-(2-nitrophenethyl)-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.78-2.86 (m, 6H), 3.16-3.23 (m, 2H), 3.63 (s, 2H), (200 MHz, 3.85 (s, 3H), 6.58 (s, 1H), 6.59 (s, 1H), 7.36-7.44 (m, CDCl₃) 2H), 7.49-7.53 (m, 1H), 7.92 (dd, J = 8.1, 1.3 Hz, 1H) ¹³C NMR 28.9, 31.0, 50.9, 55.5, 56.1, 58.8, 110.8, 112.4,  (50 MHz, 125.6, 127.4, 132.7, 133.2, 135.5, 143.8, 145.4, 149.6 CDCl₃) ESI-MS m/z 329.2 ([M + H]⁺), 351.1 ([M + Na]⁺) Compound 64 number Name 6-Methoxy-2-(3-nitrophenethyl)-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.73-2.89 (m, 6H), 2.95-3.03 (m, 2H), 3.58 (s, 2H), (200 MHz, 3.82 (s, 3H), 5.73 (s, 1H), 6.55 (s, 2H), 7.42 (t, J = 7.8 CDCl₃) Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 8.03-8.09 (m, 2H) ¹³C NMR 28.8, 33.6, 51.2, 55.6, 56.1, 59.4, 110.8, 112.4,  (50 MHz, 121.4, 123.7, 125.5, 127.0, 129.4, 135.3, 142.5, 143.9, CDCl₃) 145.5, 148.4 ESI-MS m/z 329.2 ([M + H]⁺), 351.1 ([M + Na]⁺) Compound 65 number Name 6-Methoxy-2-(4-nitrophenethyl)-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.74-2.86 (m, 6H), 2.97-3.04 (m, 2H), 3.60 (s, 2H), (200 MHz, 3.85 (s, 3H), 6.57 (s, 2H), 7.36-7.43 (m, 2H), 8.11-8.18 CDCl₃) (m, 2H) ¹³C NMR 28.8, 33.9, 51.2, 55.6, 56.1, 59.3, 110.8, 112.4,  (50 MHz, 123.8, 125.5, 127.0, 129.7, 143.9, 145.5, 146.6, 148.5 CDCl₃) ESI-MS ESIMS m/z 329.1 ([M + H]⁺) Compound 66 number Name 2-(4-Chlorophenethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.66-2.93 (m, 8H), 3.58 (s, 2H), 3.83 (s, 3H), 6.54 (200 MHz, (s, 1H), 6.56 (s, 1H), 7.11-7.19 (m, 2H), 7.21-7.28 (m, CDCl₃) 2H) ¹³C NMR 28.7, 33.3, 51.2, 55.5, 56.0, 60.0, 110.8, 112.5,  (50 MHz, 125.4, 127.0, 128.6, 130.2, 131.9, 138.9, 143.9, 145.5 CDCl₃) EIHR-MS calcd for C₁₈H₂₀ClNO₂ [M], 317.1183; found, 317.1180 Compound 67 number Name 2-(2,4-Dichlorophenethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.63-2.91 (m, 8H), 3.61 (s, 2H), 3.83 (s, 3H), 6.56 (200 MHz, (s, 2H), 7.15-7.24(m, 2H), 7.33-7.43 (m, 1H) CDCl₃) ¹³C NMR 28.8, 31.0, 51.0, 55.5, 56.0, 57.8, 110.8, 112.5,  (50 MHz, 125.5, 127.1, 127.2, 129.3, 131.7, 132.6, 134.8, 136.6, CDCl₃) 143.9, 145.4 EIHR-MS calcd for C₁₈H₁₉Cl₂NO₂ [M]⁺, 351.0793; found, 351.0799 Compound 68 number Name 2-(4-Bromophenethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.67-2.92 (m, 8H), 3.59 (s, 2H), 3.84 (s, 3H), 6.57 (200 MHz, (s, 2H), 7.07-7.15 (m, 2H), 7.37-7.44 (m, 2H) CDCl₃) ¹³C NMR 28.8, 33.5, 51.2, 55.6, 56.1, 60.0, 110.8, 112.4,  (50 MHz, 120.0, 125.5, 127.2, 130.6, 130.6, 139.5, 143.9, 145.4 CDCl₃) EIHR-MS calcd for C₁₈H₂₀BrNO₂ [M]⁺, 313.0677; found, 313.0676 Compound 69 number Name 2-(3-Bromophenethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.67-2.93 (m, 8H), 3.59 (s, 2H), 3.84 (s, 3H), 6.57 (200 MHz, (s, 2H), 7.13-7.19 (m, 2H), 7.28-7.40 (m, 2H) CDCl₃) ¹³C NMR 28.8, 33.7, 51.2, 55.6, 56.1, 60.0, 110.8, 112.4,  (50 MHz, 122.5, 125.5, 127.2, 127.6, 129.3, 130.1, 131.9, 142.9, CDCl₃) 143.9, 145.4 EIHR-MS calcd for C₁₈H₂₀BrNO₂ [M]⁺, 313.0677; found, 313.0665 Compound 70 number Name 6-Methoxy-2-(3-Methoxyphenethyl)-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.69-2.96 (m, 8H), 3.60 (s, 2H), 3.80 (s, 3H), 3.84 (200 MHz, (s, 3H), 6.57 (s, 2H), 6.72-6.88 (m, 3H), 7.16-7.28 (m, CDCl₃) 1H) ¹³C NMR 28.8, 34.1, 51.2, 55.3, 55.6, 56.1, 60.3, 110.8, 111.5,  (50 MHz, 112.1, 112.4, 114.6, 121.2, 125.5, 127.2, 129.5, 142.1, CDCl₃) 143.8, 145.4, 159.7 EIHR-MS calcd for C₁₉H₂₃NO₃ [M]⁺, 313.1678; found, 313.1678 Compound 71 number Name 2-Heptyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol 0.85-0.88 (m, 3H), 1.18-1.50 (m, 8H), 1.50-1.70 ¹H NMR (m, 2H), 2.43-2.51 (m, 2H), 2.66-2.71 (m, 2H), (200 MHz, 2.78-2.81 (m, 2H), 3.50 (s, 2H), 3.83 (s, 3H), 6.55 (s, CDCl₃) 2H) ¹³C NMR 14.2, 22.8, 27.3, 27.8, 28.8, 29.4, 32.0, 51.2, 55.7,  (50 MHz, 56.0, 58.7, 110.8, 112.5, 125.6, 127.6, 143.8, 145.4 CDCl₃) ESI-MS m/z 278.2 ([M + H]⁺) Compound 72 number Name 6-Methoxy-2-octyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 0.88(s, 3H), 1.18-1.50 (m, 10H), 1.50-1.70(m (200 MHz, 2H), 2.43-2.51 (m, 2H), 2.66-2.71 (m, 2H), 2.78-2.81 CDCl₃) (m, 2H), 3.50 (s, 2H), 3.84 (s, 3H), 6.56 (s, 2H) ¹³C NMR 14.3, 22.8, 27.3, 27.8, 28.8, 29.4, 29.7, 32.0, 51.2,  (50 MHz, 55.8, 56.1, 58.7, 110.8, 112.5, 125.6, 127.5, CDCl₃) 143.8, 145.4 ESI-MS m/z 292.2 ([M + H]⁺) Compound 73 number Name 6-Methoxy-2-nonyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 0.88(s 3H), 1.28 (bs, 12H), 1.50-1.70(m 2H), (200 MHz, 2.43-2.51 (m, 2H), 2.69-2.72 (m, 2H), 2.79-2.81 (m, CDCl₃) 2H), 3.50 (s, 2H), 3.83 (s, 3H), 6.55 (s, 2H) ¹³C NMR 14.3, 22.8, 27.3, 27.8, 28.8, 29.4, 29.7, 32.0, 51.2,  (50 MHz, 55.7, 56.1, 58.7, 110.8, 112.5, 125.7, 127.5, CDCl₃) 143.8, 145.4 ESI-MS m/z 306.2 ([M + H]⁺) Compound 74 number Name 2-(3,4-Dimethoxyphenethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.68-2.93 (m, 8H), 3.60 (s, 2H), 3.84 (s, 3H), 3.86 (200 MHz, (s, 3H), 3.87 (s, 3H), 6.57 (s, 2H), 6.73-6.84 (m, 3H) CDCl₃) ¹³C NMR 28.8, 33.6, 51.3, 55.6, 56.0, 60.5, 110.8, 111.3,  (50 MHz, 112.1, 112.4, 120.6, 125.5, 127.2, 133.0, 143.8, 145.4, CDCl₃) 147.4, 148.9 EIHR-MS calcd for C₂₀H₂₅NO₄ [M]⁺, 343.1784; found, 343.1788 Compound 75 number Name 2-(2-Chlorophenethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.68-2.90(m, 6H), 2.98-3.11 (m, 2H), 3.63 (s, 2H), (200 MHz, 3.83 (s, 3H), 6.57 (s, 2H), 7.09-7.24 (m, 2H), 7.24-7.39 CDCl₃) (m, 2H) ¹³C NMR 28.8, 31.6, 51.0, 55.5, 56.0, 58.1, 110.8, 112.5,  (50 MHz, 125.5, 127.0, 127.2, 127.7, 129.6, 131.0, 134.1, 138.0, CDCl₃) 143.8, 145.4 ESI-MS m/z 318 ([M + H]⁺), 340 ([M + Na]⁺) EIHR-MS calcd for C₁₈H₂₁ClNO₂ [M + H]⁺, 318.1261; found, 318.1253 Compound 78 number Name 6-Methoxy-2-(3-(2-nitrophenyl)propyl)-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 1.80-2.09 (m, 2H), 2.44-2.63 (m, 2H), 2.64-2.75 (200 MHz, (m, 2H), 2.76-2.88 (m, 2H), 2.88-3.07 (m, 2H), 3.51 (s, CDCl₃) 2H), 3.83 (s, 3H), 6.55 (s, 1H), 6.56 (s, 1H), 7.28-7.43 (m, 2H), 7.45-7.58 (m, 1H), 7.83-7.95 (m, 1H) ¹³C NMR 28.2, 28.8, 31.0, 51.0, 55.7, 56.0, 57.7, 110.8, 112.4,  (50 MHz, 124.8, 125.6, 127.1, 127.4, 132.2, 133.0, 137.4, 143.8, CDCl₃) 145.4, 149.5 EIHR-MS calcd for C₁₉H₂₃N₂O₄ [M + H]⁺, 343.1658; found, 343.1661 Compound 85 number Name 8-Bromo-6-methoxy-2-(4-nitrophenethyl)-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.71-2.93 (m, 6H), 2.97-3.10 (m, 2H), 3.62 (s, 2H), (200 MHz, 3.87 (s, 3H), 6.59 (s, 1H), 7.37-7.46 (m, 2H), 8.12-8.20 CDCl₃) (m, 2H) ¹³C NMR 29.3, 33.9, 50.4, 56.1, 56.4, 59.1, 108.8, 110.1,  (50 MHz, 123.8, 126.2, 127.1, 129.7, 141.3, 145.6, 146.6, 148.4 CDCl₃) ESI-MS m/z 407 ([M + H]⁺), 429 ([M + Na]⁺) EIHR-MS calcd for C₁₈H₂₀BrN₂O₄ [M + H]⁺, 407.0606; found, 407.0585 Compound 95 number Name 8-Bromo-2-(2-chlorophenethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.72-2.93 (m, 6H), 2.98-3.15 (m, 2H), 3.66 (s, 2H), (200 MHz, 3.86 (s, 3H), 6.11 (bs, 1H), 6.58 (s, 1H), 7.10-7.25 (m, CDCl₃) 2H), 7.25-7.41 (m, 2H) ¹³C NMR 29.4, 31.6, 50.2, 56.2, 56.4, 58.0, 108.9, 110.2,  (50 MHz, 126.6, 127.0, 127.3, 127.8, 129.7, 131.0, 134.2, 138.0, CDCl₃) 141.2, 145.5 ESI-MS m/z 396 ([M + H]⁺) EIHR-MS calcd for C₁₈H₂₀BrClNO₂ [M + H]⁺, 396.0366; found, 396.0355 Compound number 96 Name 8-Bromo-2-(2-fluorophenethyl)-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 2.69-2.91 (m, 6H), 2.91-3.05 (m, 2H), 3.63 (s, 2H), (200 MHz, 3.85 (s, 3H), 6.57 (s, 1H), 6.94-7.12 (m, 2H), 7.12-7.33 CDCl₃) (m, 2H) ¹³C NMR 27.2, 29.3, 50.2, 56.2, 56.4, 58.4, 109.1, 110.2,  (50 MHz, 115.4 (J = 21.9 Hz), 124.1 (J = 3.2 Hz), 126.5, 127.0, CDCl₃) 127.2, 128.0 (J = 8.1 Hz), 131.1 (J = 5.0 Hz), 141.2, 145.6, 161.3 (J = 243 Hz) ESI-MS m/z 380 ([M + H]⁺) EIHR-MS calcd for C₁₈H₂₀BrFNO₂ [M + H]⁺, 380.0661; found, 380.0662 Compound number 98 Name 8-Bromo-6-methoxy-2-(3-(2-nitrophenyl)propyl)-1,2,3, 4-tetrahydroisoquinolin-7-ol ¹H NMR 1.86-2.11 (m, 2H), 2.51-2.75 (m, 4H), 2.75-2.90 (m, (200 MHz, 2H), 2.90-3.06 (m, 2H), 3.53 (s, 2H), 3.83 (s, 3H), 6.55 CDCl₃) (s, 1H), 7.31-7.43 (m, 2H), 7.45-7.58 (m, 1H), 7.82-7.94 (m, 1H) ¹³C NMR 28.1, 29.2, 30.9, 50.1, 56.3, 57.5, 109.1, 110.1,  (50 MHz, 124.8, 126.5, 127.1, 127.3, 132.1, 133.0, 137.3, 141.2, CDCl₃) 145.7, 149.4 ESI-MS m/z 421 ([M + H]⁺) Compound number 101 Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(2-(1-naphthyl) ethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.69-3.02 (m, 6H), 3.19-3.37 (m, 4H), 3.73 (s, 3H), (200 MHz, 3.82-3.93 (m, 6H), 6.54-6.63 (m, 1H), 6.63-6.72 (m, CDCl₃) 1H), 7.03-7.12 (m, 1H), 7.25-7.29 (m, 1H), 7.29-7.35 (m, 1H), 7.35-7.43 (m, 1H), 7.43-7.55 (m, 2H), 7.65-7.76 (m, 1H), 7.79-7.89 (m, 1H), 7.95-8.04 (m, 1H) ¹³C NMR 29.2, 31.1, 50.7, 54.3, 55.5, 55.8, 56.1, 59.2, 99.2,  (50 MHz, 104.9, 110.3, 116.3, 122.6, 123.9 (x 2), 125.1, 125.6, CDCl₃) 125.7, 126.0, 126.7, 127.0, 128.9, 132.0 (x 2), 134.0, 136.6, 141.5, 145.4, 158.2, 160.9 Compound number 102 Name 8-(2,4-Dimethoxyphenyl)-2-(2-(3-indolyl)ethyl)-6- methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.72-3.42 (m, 10H), 3.70 (s, 3H), 3.85 (s, 3H), 3.88 (200 MHz, (s, 3H), 6.53-6.70 (m, 2H), 6.73-6.87 (m, 1H), CDCl₃) 6.94-7.23 (m, 5H), 7.28-7.40 (m, 1H), 7.51-7.69 (m, 1H) Compound number 105 Name 2-(4-Nitrophenethyl)-8-(2,4-dimethoxyphenyl)-6- methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.61-2.81 (m, 4H), 2.82-2.95 (m, 4H), 3.23 (s, 2H), (200 MHz, 3.72 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 6.53-6.61 (m, CDCl₃) 2H), 6.63 (s, 1H), 6.91-7.17 (m, 1H), 7.25-7.35 (m, 2H), 8.05-8.13 (m, 2H) ¹³C NMR 29.3, 33.7, 50.7, 54.2, 55.5, 55.7, 56.0, 59.1, 99.2,  (50 MHz, 104.8, 110.2, 116.3, 122.4, 123.7, 125.0, 126.4, 129.6, CDCl₃) 131.9, 141.4, 145.2, 146.5, 148.6, 158.1, 160.8 EIHR-MS calcd for C₂₆H₂₉N₂O₆ [M + H]⁺, 465.2025; found, 465.2055 Compound number 106 Name 2-(4-Chlorophenethyl)-8-(2,4-dimethoxyphenyl)-6- methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.47-2.77 (m, 6H), 2.77-2.88 (m, 2H), 3.16 (s, 2H), (200 MHz, 3.65 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 6.47-6.54 (m, CDCl₃) 2H), 6.55 (s, 1H), 6.93-7.05 (m, 3H), 7.09-7.20 (m, 2H) ¹³C NMR 29.3, 33.3, 50.6, 54.2, 55.4, 55.7, 56.0, 59.8, 99.2,  (50 MHz, 104.8, 110.2, 116.3, 122.5, 125.1, 126.6, 128.5, 130.1, CDCl₃) 131.7, 131.9, 139.0, 141.4, 145.2, 158.1, 160.7 ESI-MS m/z 452 ([M − H]⁺), 476 ([M + Na]⁺) EIHR-MS calcd for C₂₆H27ClNO₄ [M − H]⁺, 452.1629; found, 452.1623 Compound number 107 Name 2-(2,4-Dichlorophenethyl)-8-(2,4-dimethoxyphenyl)-6- methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.54-2.65 (m, 2H), 2.69-2.95 (m, 6H), 3.26 (s, 2H), (200 MHz, 3.73 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 6.54-6.61 (m, CDCl₃) 2H), 6.63 (s, 1H), 7.02-7.07 (m, 1H), 7.12 (s, 1H), 7.12 (s, 1H), 7.30-7.33 (m, 1H) ESI-MS m/z 488 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₆Cl₂NO₄ [M − H]⁺, 486.1239; found, 486.1233 Compound number 108 Name 2-(4-Bromophenethyl)-8-(2,4-dimethoxyphenyl)-6- methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.53-2.83 (m, 6H), 2.84-2.96 (m, 2H), 3.23 (bd, (200 MHz, 2H), 3.72 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 6.53-6.62 CDCl₃) (m, 2H), 6.62 (s, 1H), 6.98-7.07 (m, 3H), 7.28-7.42 (m, 2H) ¹³C NMR 29.3, 33.4, 50.6, 54.2, 55.5, 55.7, 56.0, 59.7, 99.2,  (50 MHz, 104.8, 110.2, 116.3, 119.8, 122.5, 125.1, 126.6, 130.6, CDCl₃) 131.4, 131.9, 139.6, 141.4, 145.3, 158.2, 160.8 ESI-MS m/z 496 ([M − H]⁺) EIHR-MS calcd for C₂₆H₂₇BrNO₄ [M − H]⁺, 496.1123; found, 496.1118 Compound number 109 Name 2-(3-Bromophenethyl)-8-(2,4-dimethoxyphenyl)-6- methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.54-2.83 (m, 6H), 2.83-2.96 (m, 2H), 3.13-3.33 (200 MHz, (m, 2H), 3.72 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), CDCl₃) 6.54-6.61 (m, 2H), 6.62 (s, 1H), 6.99-7.15 (m, 3H), 7.24-7.35 (m, 1H) ¹³C NMR 29.2, 33.6, 50.6, 54.2, 55.4, 55.7, 56.0, 59.6, 99.2,  (50 MHz, 110.2, 116.3, 122.4, 122.5, 125.0, 126.5, 127.5, 129.1, CDCl₃) 130.7, 131.7, 131.9, 141.4, 142.9, 145.2, 158.1, 160.8 ESI-MS m/z 498 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₇BrNO₄ [M − H]⁺, 496.1123; found, 496.1118 Compound number 110 Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(3- methoxyphenethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.51-2.85 (m, 6H), 2.86-2.98 (m, 2H), 3.25 (s, 2H), (200 MHz, CDCl₃) 3.71 (s, 3H), 3.76 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 6.53-6.60 (m, 2H), 6.62 (s, 1H), 6.67-6.79 (m, 3H), 7.00-7.07 (m, 1H), 7.10-7.21 (m, 1H) ¹³C NMR 29.2, 33.9, 50.5, 54.1, 55.2, 55.4, 55.6, 55.9, 59.9,  (50 MHz, 99.1, 104.8, 110.1, 111.3, 114.4, 116.3, 121.1, 122.4, CDCl₃) 125.0, 126.5, 129.3, 131.8, 141.3, 142.0, 145.2, 158.0, 159.6, 160.7 ESI-MS m/z 448 ([M − H]⁺), 472 ([M + Na]⁺) EIHR-MS calcd for C₂₇H₃₁NO₅ [M]⁺, 449.2202; found, 449.2197 Compound number 111 Name 8-(2,4-Dimethoxyphenyl)-2-heptyl-6-methoxy-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 0.83-0.89 (m, 3H), 1.10-1.39 (m, 8H), 1.40-1.45 (200 MHz, CDCl₃) (m, 2H), 2.31-2.38 (m, 2H), 2.63-2.71 (m, 2H), 2.85-2.91 (m, 2H), 3.16 (s, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 5.30 (s, 1H), 6.46-6.61 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 7.02-7.06 (m, 1H) ¹³C NMR 14.2, 22.8, 27.3, 27.7, 29.4, 32.0, 50.5, 54.5, 55.5,  (50 MHz, 55.7, 56.0, 58.5, 99.2, 104.8, 110.2, 125.3, 132.0, CDCl₃) 141.3, 145.1, 158.2, 160.8 ESI-MS m/z 414.3 ([M + H]⁺) Compound number 112 Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-2-octyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 0.83-0.89 (m, 3H), 1.10-1.38 (m, 10H), 1.40-1.55 (200 MHz, (m, 2H), 2.31-2.38 (m, 2H), 2.63-2.71 (m, 2H), CDCl₃) 2.85-2.91 (m, 2H), 3.16 (s, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 5.30 (s, 1H), 6.55-6.61 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 7.02-7.06 (m, 1H) ¹³C NMR 14.2, 22.8, 27.2, 27.7, 29.4 (x 2), 29.6, 31.9, 50.5,  (50 MHz, 54.4, 55.5, 55.7, 56.0, 58.4, 99.2, 104.8, 110.2, 125.3, CDCl₃) 126.9, 132.0, 141.4, 145.2, 158.2 ESI-MS m/s 428.3 ([M + H]⁺) Compound number 113 Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-2-nonyl-1,2,3,4- tetrahydroisoquinolin-7-ol ¹H NMR 0.84-0.90 (m, 3H), 1.24 (bs, 12H), 1.40-1.55 (m, (200 MHz, 2H), 2.31-2.38 (m, 2H), 2.61-2.71 (m, 2H), 2.85-2.91 CDCl₃) (m, 2H), 3.16 (s, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 5.29 (s, 1H), 6.55-6.61 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 7.02-7.06 (m, 1H) ¹³C NMR 14.2, 22.8, 27.2, 27.7, 29.4, 29.7, 32.0, 50.5, 54.5,  (50 MHz, 55.5, 55.7, 56.0, 58.4, 99.2, 104.8, 110.2, 122.5, 125.3, CDCl₃) 127.0, 131.9, 141.4, 145.2, 158.2, 160.7 ESI-MS m/z 442.3 ([M + H]⁺) Compound number 114 Name 2-(3,4-Dimethoxyphenethyl)-8-(2,4-dimethoxyphenyl)- 6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.54-2.84 (m, 6H), 2.85-2.97 (m, 2H), 3.26 (bd, (200 MHz, 2H), 3.71 (s, 3H), 3.83 (s, 3H), 3.83 (s, 6H), 3.86 (s, CDCl₃) 3H), 6.53-6.60 (m, 2H), 6.62 (s, 1H), 6.65-6.79 (m, 3H), 7.00-7.07 (m, 1H) ¹³C NMR 29.2, 33.5, 50.5, 54.1, 55.3, 55.6, 55.8, 55.9, 60.1,  (50 MHz, 99.0, 104.7, 110.1, 111.1, 111.9, 116.3, 120.5, 122.4, CDCl₃) 125.0, 126.5, 131.8, 133.0, 141.3, 145.1, 147.2, 148.7, 158.0, 160.6 ESI-MS m/z 478 ([M − H]⁺), 502 ([M + Na]⁺) EIHR-MS calcd for C₂₈H₃₃NO₆ [M]⁺, 479.2308; found, 479.2302 Compound number 115 Name 2-(2-Chlorophenethyl)-8-(2,4-dimethoxyphenyl)-6- methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.48-2.60 (m, 2H), 2.63-2.93 (m, 6H), 3.20 (s, 2H), (200 MHz, 3.63 (s, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 6.44-6.52 (m, CDCl₃) 2H), 6.54 (s, 1H), 6.92-7.14 (m, 4H), 7.15-7.25 (m, 1H) ¹³C NMR 29.2, 31.5, 50.4, 54.2, 55.4, 55.6, 55.9, 57.9, 99.1,  (50 MHz, 104.7, 110.1, 116.3, 122.5, 125.0, 126.7, 126.8, 127.5, CDCl₃) 129.4, 130.8, 131.9, 134.0, 138.0, 141.4, 145.2, 158.1, 160.7 EIHR-MS calcd for C₂₆H₂₉ClNO₄ [M + H]⁺, 454.1785; found, 454.1799 Compound number 119 Name 8-(2,4-Dimethoxyphenyl)-2-(4-fluorophenethyl)-6- methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.54-2.82 (m, 6H), 2.85-2.96 (m, 2H), 3.24 (d, J = (200 MHz, 2.1 Hz, 2H), 3.71 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), CDCl₃) 6.53-6.60 (m, 2H), 6.62 (s, 1H), 6.84-6.97 (m, 2H), 7.00-7.14 (m, 3H) ¹³C NMR 29.3, 33.3, 50.7, 54.3, 55.5, 55.8, 56.1, 60.1, 99.3,  (50 MHz, 104.9, 110.3, 115.0, 115.4, 116.4, 122.7, 125.1, 126.6, CDCl₃) 130.1, 130.3, 132.0, 136.2, 141.6, 145.4, 158.2, 160.9, 161.5 (d, J = 242 Hz) Compound number 120 Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(4- methoxyphenethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.54-2.80 (m, 6H), 2.84-2.93 (m, 2H), 3.25 (s, 2H), (200 MHz, 3.71 (s, 3H), 3.76 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), CDCl₃) 6.54-6.60 (m, 2H), 6.62 (s, 1H), 6.75-6.83 (m, 2H), 7.01-7.11 (m, 3H) ¹³C NMR 29.3, 33.1, 50.6, 54.2, 55.3, 55.4, 55.7, 56.0, 60.4,  (50 MHz, 99.1, 104.8, 110.2, 113.8, 116.4, 122.5, 125.1, 126.7, CDCl₃) 129.6, 131.9, 132.6, 141.4, 145.2, 157.9, 158.1, 160.7 ESI-MS m/z 448 ([M − H]⁺), 472 ([M + Na]⁺) EIHR-MS calcd for C₂₇H₃₁NO₅ [M], 448.2124; found, 448.2118 Compound number 121 Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(4- methylphenethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.29 (s, 3H), 2.55-2.84 (m, 6H), 2.84-2.96 (m, 2H), (200 MHz, 3.25 (bd, 2H), 3.71 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), CDCl₃) 6.54-6.60 (m, 2H), 6.62 (s, 1H), 7.01 (s, 1H), 7.02-7.07 (m, 4H) ¹³C NMR 21.1, 29.3, 33.5, 50.6, 54.2, 55.4, 55.7, 56.0, 60.2,  (50 MHz, 99.1, 104.8, 110.2, 116.4, 122.5, 125.1, 126.7,128.6, CDCl₃) 129.0, 131.9, 135.5, 137.4, 141.4, 145.2, 158.1, 160.7 EIHR-MS calcd for C₂₇H₃₂NO₄ [M + H]⁺, 434.2331; found, 434.2348 Compound number 122 Name 2-(3-Chlorophenethyl)-8-(2,4-dimethoxyphenyl)-6- methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.58-2.99 (m, 8H), 3.12 (d, J = 15.4 Hz, 1H), 3.20 (200 MHz, (d, J = 15.3 Hz, 1H), 3.65 (s, 3H), 3.78 (s, 3H), 3.80 (s, CDCl₃) 3H), 6.46-6.54 (m, 2H), 6.55 (s, 1H), 6.91-7.01 (m, 2H), 7.03-7.14 (m, 3H) ¹³C NMR 29.2, 33.7, 50.6, 54.2, 55.4, 55.7, 56.0, 59.6, 99.2,  (50 MHz, 104.8, 110.1, 116.3, 122.5, 125.0, 126.2, 126.5, 127.0, CDCl₃) 128.8, 129.6, 131.9, 134.1, 141.4, 142.5, 145.2, 158.1, 160.8 EIHR-MS calcd for C₂₆H₂₉ClNO₄ [M + H]⁺, 454.1785; found, 454.1798 Compound number 123 Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(2- methoxyphenethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 2.52-2.86 (m, 6H), 2.87-2.98 (m, 2H), 3.27 (s, 2H), (200 MHz, 3.71 (s, 3H), 3.75 (s, 3H), 3.83 (s, 3H), 3.86 (s, 3H), CDCl₃) 6.53-6.61 (m, 2H), 6.62 (s, 1H), 6.76-6.89 (m, 2H), 7.01-7.19 (m, 3H) ¹³C NMR 28.1, 29.3, 50.3, 54.2, 55.2, 55.4, 55.6, 58.3, 99.1,  (50 MHz, 104.7, 104.7, 110.1, 110.3, 116.4, 120.4, 122.5, 125.2, CDCl₃) 126.9, 127.3, 128.8, 130.2, 131.9, 141.3, 145.1, 157.5, 158.1, 160.7 EIHR-MS calcd for C₂₇H₃₂NO₅ [M + H]⁺, 450.2280; found, 450.2297 Compound number 125 Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(3- phenylpropyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 1.70-1.88 (m, 2H), 2.35-2.47 (m, 2H), 2.53-2.74 (200 MHz, (m, 4H), 2.83-2.93 (m, 2H), 3.14 (d, J = 15.2 Hz, 1H), CDCl₃) 3.23 (d, J = 15.2 Hz, 1H), 3.71 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 5.33 (s, 1H), 6.54-6.60 (m, 2H), 6.61 (s, 1H), 7.00-7.06 (m, 1H), 7.10-7.20 (m, 3H), 7.21-7.31 (m, 2H) ¹³C NMR 28.7, 29.2, 33.7, 50.5, 54.2, 55.4, 55.7, 56.0, 57.5,  (50 MHz, 99.1, 104.7, 110.3, 116.3, 122.5, 125.3, 127.0, 128.2, CDCl₃) 129.3, 132.0, 138.6, 141.4, 145.2, 158.1, 160.8 EIHR-MS calcd for C₂₇H₃₂NO₄ [M + H]⁺, 434.2331; found, 434.2356 Compound number 142 Name 6-Methoxy-8-(2-methoxyphenyl)-2-(3-(2-nitrophenyl) propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR 1.69-1.90 (m, 2H), 2.34-2.51 (m, 2H), 2.60-2.78 (200 MHz, (m, 2H), 2.78-2.99 (m. 4H), 3.13 (d, J = 15.2 Hz, 1H), CDCl₃) 3.23 (d, J = 15.2 Hz, 1H), 3.76 (s, 3H), 3.88 (s, 3H), 6.64 (s, 1H), 6.96-7.10 (m, 2H), 7.15 (dd, J = 7.3, 1.9 Hz, 1H), 7.24-7.29 (m, 1H), 7.32-7.40 (m, 1H), 7.61-7.76 (m, 2H), 7.82-7.92 (m, 1H) ¹³C NMR 28.1, 29.3, 30.8, 50.2, 54.3, 55.7, 56.0, 57.3, 110.3,  (50 MHz, 111.4, 120.9, 122.8, 124.1, 124.7, 125.4, 126.3, 127.0, CDCl₃) 129.4, 131.6, 132.1, 132.9, 137.4, 141.1, 145.2, 149.4, 157.1 ESI-MS m/z 449 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₉N₂O₅ [M + H]⁺, 449.2076; found, 449.2098 Compound number 150 Name 8-Bromo-6,7-dimethoxy-2-phenethyl-1,2,3,4- tetrahydroisoquinoline ¹H NMR 2.71-2.94 (m, 8H), 3.63 (s, 2H), 3.82 (s, 3H), 3.83 (200 MHz, (s, 3H), 6.63 (s, 1H), 7.20-7.31 (m, 5H) CDCl₃) ¹³C NMR 29.7, 34.1, 50.2, 56.1, 56.4, 60.2, 60.6, 111.7, 118.2,  (50 MHz, 126.2, 126.8, 128.5, 128.8, 131.9, 140.4, 144.6, 151.7 CDCl₃) ESI-MS m/z 376 ([M + H]⁺), 398 ([M + Na]⁺) EIHR-MS calcd for C₁₉H₂₃BrNO₂ [M + H]⁺, 376.0912; found, 376.0905 Compound number 152 Name 8-Bromo-6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4- tetrahydroisoquinoline ¹H NMR 2.69-2.80 (m, 2H), 2.80-2.93 (m, 4H), 2.96-3.10 (200 MHz, (m, 2H), 3.61 (s, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 6.64 CDCl₃) (s, 1H), 7.36-7.46 (m, 2H), 8.10-8.19 (m, 2H) ¹³C NMR 29.6, 33.9, 50.2, 56.2, 56.3, 59.1, 60.6, 111.7, 118.2,  (50 MHz, 123.8, 126.5, 129.7, 131.8, 144.7, 146.6, 148.4, 151.8 CDCl₃) ESI-MS m/z 421 ([M + H]⁺), 443 ([M + Na]⁺) EIHR-MS calcd for C₁₉H₂₂BrN₂O₄ [M + H]⁺, 421.0763; found, 421.0730 Compound number 153 Name 8-Bromo-2-(2-chlorophenethyl)-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline ¹H NMR 2.73-2.95 (m, 6H), 2.99-3.13 (m, 2H), 3.66 (s, 2H), (200 MHz, 3.82 (s, 3H), 3.84 (s, 3H), 6.64 (s, 1H), 7.10-7.25 (m, CDCl₃) 2H), 7.29-7.39 (m, 2H) ¹³C NMR 29.7, 31.7, 50.0, 56.2, 56.4, 58.0, 60.6, 111.8, 118.3,  (50 MHz, 126.9, 127.0, 127.8, 129.6, 131.0, 131.9, 134.2, 138.0, CDCl₃) 144.6, 151.7 ESI-MS m/z 410 ([M + H]⁺) EIHR-MS calcd for C₁₉H₂₂BrClNO₂ [M + H]⁺, 410.0522; found, 410.0494 Compound number 154 Name 8-Bromo-2-(2-fluorophenethyl)-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline ¹H NMR 2.69-2.90 (m. 6H), 2.90-3.04 (m, 2H), 3.63 (s, 2H), (200 MHz, 3.82 (s, 3H), 3.84 (s, 3H), 6.63 (s, 1H), 6.95-7.12 (m, CDCl₃) 2H), 7.12-7.33 (m, 2H) ¹³C NMR 27.3, 29.7, 50.0, 56.2, 56.4, 58.4, 60.6, 111.7, 115.3  (50 MHz, (J = 22.0 Hz), 118.2, 124.2, 126.8, 127.1 (J = 16.1 Hz), CDCl₃) 127.9 (J = 8.0 Hz),131.1 (J = 4.8 Hz), 131.9, 144.6, 151.6, 161.3 (J = 243 Hz) ESI-MS m/z 394 ([M + H]⁺) EIHR-MS calcd for C₁₉H₂₂BrFNO₂ [M + H]⁺, 394.0818; found, 394.0806 Compound number 157 Name 8-(2-Fluorophenyl)-6,7-dimethoxy-2-phenethyl-1,2,3,4- tetrahydroisoquinoline ¹H NMR 2.54-2.88 (m, 6H), 2.88-3.05 (m, 2H), 3.19 (d, J = (200 MHz, 15.0 Hz ,1H), 3.30 (d, J = 15.0 Hz, 1H), 3.56 (s, 3H), CDCl₃) 3.86 (s, 3H), 6.73 (s, 1H), 7.03-7.41 (m, 9H) ¹³C NMR 29.5, 34.0, 50.3, 54.2, 55.9, 60.0, 60.8, 112.5, 115.6  (50 MHz, (J = 22.2 Hz), 123.6, 124.0 (J = 3.2 Hz), 126.1, 128.1, CDCl₃) 128.4, 128.7, 129.4, 130.1, 131.8 (J = 3.5 Hz), 140.4, 145.2, 151.0, 159.9 (J = 234 Hz) ESI-MS m/z 392 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₇FNO₂ [M + H]⁺, 390.2026; found, 390.2014 Compound number 158 Name 8-(2-Chlorophenyl)-6,7-dimethoxy-2-phenethyl- 1,2,3,4-tetrahydroisoquinoline ¹H NMR 2.55-2.68 (m, 2H), 2.68-2.89 (m. 4H), 2.89-3.00 (200 MHz, (m, 2H), 3.17 (s, 2H), 3.58 (s, 3H), 3.87 (s, 3H), 6.73 CDCl₃) (s, 1H), 7.10-7.27 (m, 6H), 7.27-7.36 (m, 2H), 7.43-7.53 (m, 1H) ¹³C NMR 29.5, 34.0, 50.4, 53.9, 55.9, 60.0, 60.7, 112.3,  (50 MHz, 125.7, 126.1, 126.8, 128.4, 128.8, 129.0, 129.5, 130.1, CDCl₃) 131.3, 131.8, 133.8, 135.6, 140.4, 144.6, 151.0 ESI-MS m/z 408 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₇ClNO₂ [M + H]⁺, 408.1730; found, 408.1730 Compound number 159 Name 6,7-Dimethoxy-8-(2-methoxyphenyl)-2-phenethyl- 1,2,3,4-tetrahydroisoquinoline ¹H NMR 2.54-2.87 (m, 6H), 2.87-3.00 (m. 2H), 3.15 (d, J = (200 MHz, 15.1 Hz, 1H), 3.26 (d, J = 15.1 Hz, 1H), 3.52 (s, 3H), CDCl₃) 3.74 (s, 3H), 3.86 (s, 3H), 6.69 (s, 1H), 6.92-7.05 (m, 2H), 7.06-7.15 (m, 2H), 7.15-7.29 (m, 4H), 7.29-7.40 (m, 1H) ¹³C NMR 29.6, 34.0, 50.4, 54.1, 55.5, 55.8, 60.1, 60.6, 110.8,  (50 MHz, 111.8, 120.6, 125.2, 126.1, 126.3, 128.4, 128.8, 128.9, CDCl₃) 129.6, 131.2, 140.5, 145.0, 151.0, 156.9 ESI-MS m/z 404 ([M + H]⁺) EIHR-MS calcd for C₂₆H₃₀NO₃ [M + H]⁺, 404.2226; found, 404.2217 Compound number 165 Name 2-(2-Fluorophenethyl)-8-(2-fluorophenyl)-6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR 2.56-2.68 (m, 2H), 2.68-2.88 (m, 4H), 2.88-3.01 (200 MHz, (m. 2H), 3.20 (d, J = 15.1 Hz, 1H), 3.31 (d, J = 15.1 CDCl₃) Hz, 1H), 3.56 (s, 3H), 3.86 (s, 3H), 6.73 (s, 1H), 6.89-7.06 (m, 2H), 7.09-7.24 (m, 5H), 7.28-7.42 (m, 1H) ¹³C NMR 27.2, 29.5, 50.1, 54.2, 55.9, 58.2, 60.8, 112.6?+0  (50 MHz, 115.3 (J = 21.7 Hz), 115.6 (J = 22.0 Hz), 123.6, 124.0 CDCl₃) (J = 3.2 Hz), 126.1, 127.2 (J = 15.9 Hz), 127.8 (J = 7.9 Hz), 128.1, 129.5 (J = 7.9 Hz), 130.2, 131.0 (J = 4.9 Hz), 131.8 (J = 3.0 Hz), 145.2, 151.1, 159.9 (J = 244 Hz), 161.2 (J = 243 Hz) ESI-MS m/z 410 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₆F₂NO₂ [M + H]⁺, 410.1932; found, 410.1927 Compound number 166 Name 8-(2-Chlorophenyl)-2-(2-fluorophenethyl)-6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR 2.55-2.68 (m, 2H), 2.68-2.88 (m, 4H), 2.88-3.00 (200 MHz, (m. 2H), 3.18 (s, 2H), 3.57 (s, 3H), 3.87 (s, 3H), 6.73 CDCl₃) (s, 1H), 6.88-7.05 (m, 2H), 7.06-7.24 (m, 3H), 7.26-7.36 (m, 2H), 7.42-7.52 (m, 1H) ¹³C NMR 27.2, 29.4, 50.1, 53.9, 55.9, 58.1, 60.7, 112.4, 115.3  (50 MHz, (J = 22.0 Hz), 124.0 (J = 3.2 Hz), 125.6, 126.8, 127.2 CDCl₃) (J = 16.0 Hz), 127.8 (J = 7.9 Hz), 129.0, 129.5, 130.1, 131.0 (J = 4.9 Hz), 131.3, 131.8, 133.8, 135.6, 144.7, 151.0, 161.2 (J = 243 Hz) ESI-MS m/z 426 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₆ClFNO₂ [M + H]⁺, 426.1636; found, 426.1634 Compound number 167 Name 2-(2-Chlorophenethyl)-8-(2-fluorophenyl)-6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR 2.55-2.70 (m, 2H), 2.70-3.02 (m, 6H), 3.22 (d, J = (200 MHz, 15.1 Hz, 1H), 3.32 (d, J = 15.1 Hz, 1H), 3.56 (s, 3H), CDCl₃) 3.87(s, 3H), 6.73 (s, 1H), 7.04-7.24(m, 6H), 7.24-7.42 (m, 2H) ¹³C NMR 29.5, 31.5, 50.1, 54.3, 55.9, 57.9, 60.8, 112.5, 115.6  (50 MHz, (J = 22.1 Hz), 123.6, 124.1, 126.1, 126.9, 127.6, 128.1, CDCl₃) 129.4 (J = 7.1 Hz), 129.5, 130.1, 130.9, 131.9, 134.0, 137.9, 145.2, 151.1, 159.9 (J = 243 Hz) ESI-MS m/z 426 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₆ClFNO₂ [M + H]⁺, 426.1636; found, 426.1640 Compound number 168 Name 2-(2-Chlorophenethyl)-8-(2-chlorophenyl)-6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR 2.53-2.69 (m, 2H), 2.69-3.03 (m, 6H), 3.20 (s, 2H), (200 MHz, 3.57 (s, 3H), 3.87 (s, 3H), 6.73 (s, 1H), 7.02-7.23 (m, CDCl₃) 4H), 7.23-7.38 (m, 3H), 7.42-7.54 (m, 1H) ¹³C NMR 29.5, 31.6, 50.2, 54.0, 55.9, 57.9, 60.7, 112.4,  (50 MHz, 125.7, 126.8, 127.6, 129.0, 129.5, 130.1, 130.9, 131.3, CDCl₃) 131.8, 133.8, 134.1, 135.7, 138.0, 144.7, 151.0 ESI-MS m/z 442 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₆Cl₂NO₂ [M + H]⁺, 442.1341; found, 442.1335 Compound number 171 Name 8-(2-Fluorophenyl)-6,7-dimethoxy-2-(4- nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline ¹H NMR 2.62-3.00 (m, 8H), 3.20 (dd, J = 17.9, 15.1 Hz, 2H), (200 MHz, 3.55 (s, 3H), 3.87 (s, 3H), 6.73 (s, 1H), 7.07-7.24 (m, CDCl₃) 3H), 7.25-7.42 (m, 3H), 8.04-8.15 (m, 2H) ¹³C NMR 29.6, 34.1, 50.5, 54.2, 55.9, 59.0, 60.8, 112.5, 115.7  (50 MHz, (J = 22.3 Hz), 123.5, 123.7 (J = 17.4 Hz), 124.0, 125.8, CDCl₃) 128.1, 129.5 (J = 7.3 Hz), 129.6, 130.0, 131.8 (J = 3.1 Hz), 145.3, 151.0, 161.2 (J = 243 Hz ESI-MS m/z 437 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₆FN₂O₄ [M + H]⁺, 437.1877; found, 437.1874 Compound number 172 Name 8-(2-Chlorophenyl)-6,7-dimethoxy-2-(4- nitrophenethyl)-1,2,3,4-tetrahydroisoquinolinee ¹H NMR 2.61-2.99 (m, 8H), 3.13 (dd, J = 16.6, 15.2 Hz, 2H), (200 MHz, 3.57 (s, 3H), 3.87 (s, 3H), 6.73 (s, 1H), 7.11-7.22 (m, CDCl₃) 2H), 7.24-7.37 (m, 4H), 7.47-7.52 (m, 1H), 8.03-8.14 (m, 2H) ¹³C NMR 29.5, 34.0, 50.6, 53.9, 58.9, 60.7, 112.3, 123.7,  (50 MHz, 125.3, 126.9, 129.0. 129.6, 130.0, 131.3, 131.8, 133.7, CDCl₃) 135.6, 144.7, 146.5, 148.6, 151.1 ESI-MS m/z 453 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₆ClN₂O₄ [M + H]⁺, 453.1581; found, 453.1571 Compound number 173 Name 6,7-Dimethoxy-8-(2-methoxyphenyl)-2-(4- nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline ¹H NMR 2.59-3.00 (m, 8H), 3.17 (dd, J = 19.8, 15.0 Hz, 2H), (200 MHz, 3.52 (s, 3H), 3.73 (s, 3H), 3.86 (s, 3H), 6.69 (s, 1H), CDCl₃) 6.92-7.04 (m, 2H), 7.07 (dd, J = 7.4, 2.2 Hz, 1H), 7.26-7.41 (m, 3H), 8.03-8.14 (m, 2H) ¹³C NMR 29.6, 34.0, 50.6, 54.1, 55.5, 55.9, 59.0, 60.6, 110.8,  (50 MHz, 111.8, 120.6, 123.6, 125.1, 126.0, 129.0, 129.6, 131.1, CDCl₃) 145.1, 146.5, 148.7, 151.1, 156.9 ESI-MS m/z 449 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₉N₂O₅ [M + H]⁺, 449.2076; found, 449.2071

The 5-HT₇ receptor binding affinity, 5-HT2A receptor binding affinity, and log D data of compounds 6-10 are shown in Table 8.

TABLE 8 The receptor binding affinity and log D of 6-10 compound K_(i) (nM), 5-HT₇R K_(i) (nM), 5-HT_(2A)R log D  6 3.5 2.2 3.98  7 1.4 70 3.66  8 5.8 >1000 1.68  9 4.9 >1000 1.70 10 7.1 >1000 2.93

Animals

Specific pathogen free C57BL/6 mice (4-6 weeks of age) obtained from the Animal Center of the National Taiwan University were used for the study. Animals were raised in a temperature-controlled room (20±2° C.) with 12/12-h light/dark cycles, and fed with regular mice chow and water ad libitum. All experimental procedures were approved by the Animal Care and Use Committee of the National Taiwan University.

Reagents

Novel 8-phenyl-isoquinoline derivatives were prepared by the procedures described below. SB-269970 hydrochloride (SB7) (a 5-HT₇R antagonist, Sigma #S7389), alosetron hydrochloride (ALN) (a 5-HT₃R antagonist, Sigma #SML0346), and loperamide hydrochloride (LPM) (a μ-opioid receptor agonist; Sigma #L4762) were intraperitoneally (i.p.) or perorally (p.o.) administered by a single dose or multiple doses to mice for the analysis of intestinal pain.

Two Experimental Models of Visceral Hypersensitivity

(1) Dual Challenge of Giardia Postinfection Combined with Water Avoidance Stress

Two animal models of IBS that had shown visceral hypersensitivity were used in the study, including dual challenge of postinfection combined with psychological stress, and post-inflammation. In the first model, mice were divided into two groups, including one group subjected to dual triggers of Giardia postinfection and water avoidance stress (GW) and the one group pair-fed with saline and non-handled (PN) as uninfected unstressed normal controls. Axenic Giardia lamblia trophozoites (strain GS/M, ATCC 50581) were cultured in vitro and harvested at log-phase as described in Singer et al., (T-cell-dependent control of acute Giardia lamblia infections in mice. Infect. Immun. 2000;68:170-175) and Davids et al. (Polymeric immunoglobulin receptor in intestinal immune defense against the lumen-dwelling protozoan parasite Giardia. J Immunol 2006; 177:6281-6290). Mice were orally gavaged with 10⁷ Giardia trophozoites suspended in 0.2 ml of sterile phosphate-buffered saline (PBS) or pair-fed with the same volume of PBS. The status of Giardia infection was verified after 4-7 days by enumeration of motile trophozoites in the small intestine following a cold-shock protocol (disclosed in Scott K G, Yu L C H, Buret A G. Role of CD8+ and CD4+ T lymphocytes in jejunal mucosal injury during murine giardiasis. Infect. Immun. 2004; 72:3536-3542 and Scott K G, Meddings J B, Kirk D R, et al. Intestinal infection with Giardia spp. reduces epithelial barrier function in a myosin light chain kinase-dependent fashion. Gastroenterology 2002; 123:1179-1190). On the sixth week postinfection in which the trophozoites could not be detected in the small intestine (post-clearance phase), mice were subjected to chronic psychological stress. The procedure of WAS involved placing the mouse on a platform (3×6 cm) in the center of a container (56 ×50 cm) with 3 cm (vertical height) of room temperature water. Mice remained on the platform for 1 hr to avoid water immersion as a psychological stress without physical harm. The 1-hr stress sessions were carried out for 10 consecutive days to mimic chronic repeated stress, and were performed between 9:00 and 12:00 to minimize the effect of the circadian rhythm. Uninfected and unstressed non-handled animals were kept in their cages as normal controls. On the last day of the stress session, intestinal pain was measured in mice.

For testing of anti-nociceptive effects in the GW model, mice were administered novel 5-HT₇R ligands by a single dose 90 or 240 minutes prior to intestinal pain measurement. In additional settings, the novel ligands were repeatedly administered for 10 consecutive days 30 minutes before the start of each stress session and intestinal pain was measured immediately after the last stress session.

(2) Postinflammation Model

In the second model, intestinal inflammation was induced by intracolonic administration of 10% 2,4,6-trinotrobenzene sulfonic acid (TNBS) in 0.2 ml of 50% ethanol (Sigma-Aldrich, St. Louis, Mo., USA) via a 22-gauge feeding needle. Sham controls were given PBS in the same volume. Intestinal inflammatory parameters and pain levels were measured on various time points after TNBS administration.

For testing of anti-nociceptive effects in the post-TNBS model, mice were administered with novel 5-HT₇R ligands by a single dose at 90 or 240 minutes before or by repeated administration of multiple doses for 10 consecutive days prior to intestinal pain measurement.

Assessment of Pain Sensation to Colorectal Distension

Abdominal pain was measured by visceromoter response (VMR) to colorectal distension (CRD) in mice following previously described methods with slight modification (Lu C L, Hsieh J C, Dun N J, et al. Estrogen rapidly modulates 5-hydroxytrytophan-induced visceral hypersensitivity via GPR30 in rats. Gastroenterology 2009; 137:1040-1050; Hong S, Zheng G, Wu X, et al. Corticosterone mediates reciprocal changes in CB 1 and TRPV1 receptors in primary sensory neurons in the chronically stressed rat. Gastroenterology 2011; 140:627-637 e4). Briefly, electrodes made from Teflon-coated stainless steel wire (A-M systems, Carlsborg, Wash.) were implanted in the abdominal external oblique muscles of mice at least 15 days prior to VMR experiments. The electrodes were exteriorized onto the back of the neck. Mice were habituated in the plexiglass cylinder for 30 minutes per day for 3 consecutive days before VMR experiments. The cylinder was used for partial restraint of conscious mice during the CRD experiments. For recording, electrodes were connected to an electromyogram acquisition system (AD instruments, New south wales, Australia). The colon was distended by inflating a balloon catheter inserted intra-anally such that it ended 1.5 cm proximal to the anus. Mice were subjected to four 10-second distensions (15, 40, and 65 mmHg) with 3-min rest intervals. The electromyographic (EMG) activity was amplified and digitized using a transducer (AD instruments) connected to a P511 AC amplifier (Grass instruments, Calif., USA) and Powerlab device with Chart 5 software (AD instruments). The EMG activity was rectified, and the response was recorded as the increase in the area under the curve (AUC) of the EMG amplitude during CRD versus the baseline period.

Histopathological Examination

Intestinal tissues were fixed in 4% paraformaldehyde (PFA) and embedded in paraffin wax with proper orientation of the crypt to villus axis before sectioning. Sections of 5-μm thickness were deparaffinized with xylene and graded ethanol, stained with hematoxylin and eosin (H&E), and observed under a light microscope.

Reverse Transcription Polymerase Chain Reaction

Total RNA was extracted from tissue samples using Trizol reagent (Invitrogen) according to the manufacturer's instructions. The RNA (2 μg) was reversely transcribed with oligo(dT)15 using RevertAid™ First Strant cDNA Synthesis kit (Thermo) in 20 μL reaction volume. The resulting cDNA corresponding to 0.1 μg of initial RNA was then subjected to PCR by the addition of master mix containing 1× PCR buffer, 1 U DreamTaq™ DNA Polymerase, 0.2 mM dNTPs mixture, 0.4 μM upstream primer, and 0.4 μM downstream primer. The specific primer pairs for PCR reaction were as follows: mouse 5-HT₇R (forward, 5′-TCTTCGGATGGGCTCAGAATGT-3′ and reverse, 5′ -AACTTGTGTTTGGCTGCGCT-3′), and β-actin (forward, 5′-GGGAAATCGTGCGTGAC-3′ and reverse, 5′-CAAGAAGGAAGGCTGGAA-3′) (as disclosed in Forcen R, Latorre E, Pardo J, et al. Toll-like receptors 2 and 4 modulate the contractile response induced by serotonin in mouse ileum: analysis of the serotonin receptors involved. Neurogastroenterol Motil 2015; 27:1258-66). The DNA thermal cycler was programmed to perform a protocol as follows: 95° C. for 3 min for 1 cycle; 95° C. for 30 sec (denaturation), 55° C. for 30 sec (annealing), and 72° C. for 30 sec (extension) for 30 cycles; and 72° C. for 7 min for final extension. Negative controls were performed with samples lacking cDNA that was not reversely transcribed. RT-PCR products were then electrophoresed in a 1.5% agarose gel in the presence of 0.5 μg/mL ethidium bromide, visualized with an ultraviolet transilluminator, and photographs were taken. The intensity of the DNA bands was analyzed using the Gel-Pro Analyzer 4.0 software.

Immunofluorescent Staining of 5-HT₇R

Deparaffinized histological slides were incubated with 10 mM Tri-sodium citrate buffer (pH 6.0) containing 0.05% Tween-20 and boiled in microwave. Sections were left at room temperature to cool down. After quenching with 1 mg/ml NaBH4 in PBS (pH 8.0) for 515 minutes at room temperature, tissues were blocked with 1% bovine serum albumin for 2 hours at room temperature. Tissue sections were incubated with primary antibodies, rabbit polyclonal anti-5-HT₇R (1:300, Abcam), rabbit PGP9.5 antibody (1:250, GeneTex) or isotype controls overnight at 4° C. The sections were washed with PBS and incubated with a secondary goat anti-rabbit IgG conjugated to Alexa Fluor 488 (1:250, Molecular Probes) for one hour at room temperature. The tissues were then incubated with a Hoechst dye (1 μg/ml in PBS) (Sigma) for another 30 minutes. The slides were observed under a fluorescent microscope and the images were captured.

Western Blotting

Intestinal mucosal proteins were extracted with complete radio-immunoprecipitation (RIPA) buffer and subjected to SDS/polyacrylamide gel electrophoresis (PAGE) (4-13% polyacrylamide) (as described in Kuo W T, Lee T C, Yang H Y, et al. LPS receptor subunits have antagonistic roles in epithelial apoptosis and colonic carcinogenesis. Cell Death Differ 2015; 22:1590-1604; Wu L L, Peng W H, Kuo W T, et al. Commensal Bacterial Endocytosis in Epithelial Cells Is Dependent on Myosin Light Chain Kinase-Activated Brush Border Fanning by Interferon-gamma. Am J Pathol 2014; 184:2260-2274; and Yu L C, Shih Y A, Wu L L, et al. Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis. Am J Physiol Gastrointest Liver Physiol 2014; 307:G824-35). The resolved proteins were then electrotransferred onto PVDF or nitrocellulose membranes in a semi-dry blotter. Blots were blocked with 5% (w/v) nonfat dry milk in Tris-buffered saline (TB S) or 5% (w/v) bovine serum albumin in TBS with Tween 20 (TBS-T; 0.1% (v/v) Tween-20 in TBS) for 1 h, washed with TBS-T, and incubated with a primary antibody at 4° C. overnight. The membrane was washed and incubated with a secondary antibody for 1 h. After washing, the membranes were incubated with chemiluminescent solution and signals detected. The primary antibodies used included rabbit polyclonal anti-5-HT₇R (1:500, Abcam) and anti-β-actin (1:10000, Sigma). The secondary antibodies used were horseradish peroxidase-conjugated goat anti-rabbit IgG (1:1000, Cell Signaling).

Statistical Analysis

All values were expressed as mean ±SEM, and compared by paired Student's t test. Significance was established at P<0.05.

Intestinal Hypernociception Correlated with Upregulation of Colonic 5-HT₇R Expression in two IBS-Like Mouse Models

Two animal models of IBS-like visceral hypersensitivity were utilized to examine anti-nociceptive effects of a series of 8-phenylisoquinoline derivatives which were novel 5-HT₇R ligands. Mice were divided into two groups, one group was subjected to Giardia postinfection and water avoidance stress (GW) and another group was pair-fed and non-handled (PN) as uninfected unstressed normal controls. The visceromoter response (VMR) to colorectal distension was expressed as the area under a curve (AUC), and was determined in each mouse as an indicator of intestinal pain.

In the first model, by dual challenge of Giardia postinfection combined with psychological stress (GW) an increased abdominal pain was observed compared to normal controls (FIG. 5(A)). FIG. 5B shows representative images of the colon histology in PN and GW mice. The colonic morphology was similar between GW mice and the normal controls (FIG. 5(B)). 5-HT₇R in colonic tissues of PN and GW mice were immunostained. FIG. 5(C) shows the representative images of of 5-HT₇R staining (panel a) and quantification of 5-HT₇R immunoreactivity in muscle/nerve and mucosal layers (panel b and c). FIG. 5(D) shows the results of Western blotting showing increased 5-HT₇R protein levels in GW mice. Upregulated expression of 5-HT₇R was observed in colon tissues of GW mice (FIGS. 5(C) and 5(D)), with higher levels located at the smooth muscle, enteric nerves, and mucosal region (FIG. 5(C)).

In the second model, mice were given one bolus of colitogenic chemical TNBS or PBS intracolonically on day 0 and intestinal inflammation and pain were examined and measured on various days. These animals displayed an increased abdominal pain 7, 14 and 24 days post-TNBS (FIG. 6(A)). However, colonic inflammatory index such as myeloperoxidase activity and histopathological scores peaked by day 2, and showed resolution by day 7 (FIGS. 6B-D). Therefore, post-TNBS on day 24 was used as the time point for examination of IBS-like visceral hypersensitivity. Upregulated expression of 5-HT₇R was observed in colon tissues of TNBS mice, with higher levels located at the smooth muscle, enteric nerves, and mucosa region (FIGS. 6E and 6F).

5-HT₇R Activation is Involved in Visceral Hypersensitivity in the IBS Models

To verify the role of 5-HT₇R on visceral hypersensitivity for proof-of-concept, a putative 5-HT₇R antagonist for research use (SB-269970) was intraperitoneally (i.p., 0.5 mg/Kg) injected into the animal models and intestinal pain was measured by VMR. Administration of SB7 through i.p. significantly inhibited intestinal pain levels in mice (FIG. 7).

Anti-Nociceptive Effects of Novel 5-HT₇R Ligands

Novel 8-phenyl-isoquinoline derivatives (compounds I) targeting 5-HT₇R with high binding affinity and water solubility were synthesized (Compounds 6-10 shown in Table 8). In the initial experiments, compounds 6-10 (5-HT₇R ligands) were perorally (p.o.) administered at 5 mg/kg in GW mice to assess the inhibitory effect on abdominal pain. A single dose at 5 mg/Kg was administered 90 minutes before the analysis of VMR. All of the compounds tested showed anti-nociceptive effects, among which compound 8 exhibited the strongest inhibition of intestinal pain to baseline levels (FIG. 8).

To examine the dose response on anti-nociceptive effects, compound 8 was injected intraperitoneally (i.p.) at 0.05, and 0.5 mg/kg, or perorally (p.o.) at 1.5, and 5 mg/kg to GW mice. Dose-dependent analgesic effects were observed in GW mice by compound 8 (FIGS. 9A and 9B). To verify whether the analgesic effect was long-lasting, CYY1005 at 5 mg/kg was p.o. administered at either 1.5, 4, or 12 hours prior to pain measurement in GW mice. Reduction of pain levels was seen at three time points (FIG. 9C). Furthermore, repeated administration of compound 8 as multiple doses also decreased intestinal pain in GW mice in a dose-dependent manner (FIG. 9D).

TNBS mice were perorally (p.o.) injected with vehicle or novel 5-HT₇R ligands to assess the inhibitory effect on abdominal pain. A single dose at 5 mg/kg was administered 90 minutes before the analysis of VMR. In these TNBS mice, these novel 5-HT₇R ligands attenuated intestinal pain at a single dose by p.o. administration (FIG. 10(A)). Similarly, repeated administration of compound 8 as multiple doses also reduced intestinal pain in TNBS mice (FIG. 10(B)).

Comparison of analgesic effects and adverse response between 8-phenylisoquinoline derivatives and reference standards

The anti-nociceptive potency of compounds I (compounds 6-10) was compared with reference standards by p.o. administration in the two animal models. These compounds and reference standards included SB7 (a 5-HT₇R antagonist), alosetron (ALN, a 5-HT₃R antagonist), and loperamide (LPM, a μ-opioid receptor agonist) which were administered at 5 mg/Kg 90 minutes before pain analysis. In the GW mice, p.o. administration of ALN reduced intestinal pain but was less efficient compared to compound 8 in GW mice (FIG. 8(A)). On the other hand, p.o. administration of SB7 and LPM had no effect on intestinal nociception in GW mice (FIG. 11(A)). In the second animal model, administration of ALN, SP7, or LPM had no effect on intestinal pain in the TNBS mice (FIG. 11(B)).

All mice administered vehicle or compounds displayed normal colonic histology, except those given ALN. In 2 out of 14 mice (14%) administered ALN, hyperemia and granulocyte infiltration were observed in the colonic tissues (FIG. 11(C)).

Newly FDA-approved agents, eluxadoline (a mixed μ-opioid agonist) and rifamixin (a nonabsorbable gut-specific antibiotic) had been recent additions to the treatment options for IBS-D. These pharmaceutic agents represented molecular mechanisms or environmental factors different from the 5-HT₇R targets. It was noteworthy that any opioid agonist would pose a risk for drug addiction following long-term treatment. Compared to traditional pain-killers (e.g. non-steroidal anti-inflammatory drugs and anticholinergic agents) or anti-diarrheal opioid agonists (e.g. loperamide), this series of 8-phenyl-isoquinoline derivatives, i.e., 5-HT₇R antagonists, were more beneficial because they might peripheral-selectively act at the hypernociceptive intestine.

In this invention, 8-phenyl-isoquinoline derivatives (I) (Compounds 6-10) exhibited stronger analgesic actions without adverse effects compared to alosetron in IBS animal models, and therefore they were suitable to be used in both male and female patients as new therapeutic options for IBS treatment.

REFERENCES

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Part I

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Part II

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What is claimed is:
 1. A compound of the following general formula or a pharmaceutically acceptable salt thereof:

wherein R₁ is selected from a group consisting of hydrogen, a C₁₋₁₀ linear chain alkyl group, a C₁₋₁₀ branched chain alkyl group, (CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and (CH₂)_(n)ArR₁₀R₁₁R₁₂, wherein the n is an integer from 0 to 6, Hete is a heteroaromatic group, Ar is an aromatic group, and R₁₀, R₁₁ and R₁₂ are independently selected from a group consisting of hydrogen, a halo group, nitro group, an amino group, a cyano group, an acetyl group, a C₁₋₆ linear chain saturated alkyl group, a C₁₋₆ linear chain saturated alkoxy group and a C₁₋₆ linear chain saturated haloalkyl group; R₂ is a hydrogen or a C1-6 linear chain saturated alkyl group; and X₁, X₂, X₃, X₄ and X₅ are independently selected from a group consisting of hydrogen, a halo group, a nitro group, an amino group, a cyano group, an acetyl group, a C₁₋₆ linear chain saturated alkyl group, a C₁₋₆ branched chain saturated alkyl group, a C₁₋₆ linear chain saturated alkoxy group, a C₁₋₆ branched chain saturated alkoxy group, a C₁₋₆ linear chain saturated alkylthio group, a C₁₋₆ branched chain saturated alkylthio group, a C₁₋₆ linear chain saturated haloalkyl group and a C₁₋₆ branched chain saturated haloalkyl group.
 2. The compound as claimed in claim 1, wherein the halo group is selected from a group consisting of fluorine, chlorine, bromine and iodine.
 3. The compound as claimed in claim 1, wherein the heteroaromatic group is selected from a group consisting of a pyrrolyl group, a furanyl group, a thiophenyl group, a pyridinyl group, a pyrimidinyl group, a thiazolyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzofuranyl group, an isobenzofuranyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl group and a benzothiazolyl group.
 4. The compound as claimed in claim 1, which is selected from 6-methoxy-8-(2-methoxyphenyl)-2-(3-(4-nitrophenyl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (compound 7), 6-methoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-4-yl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (compound 8), 6-methoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-3-yl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (compound 9), and 6,7-dimethoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-4-yl)propyl)-1,2,3,4-tetrahydroisoquinoline (compound 10), or a pharmaceutically acceptable salt thereof.
 5. The compound as claimed in claim 1, which is 6-methoxy-8-(2-methoxyphenyl)-2-(3-(pyridin-4-yl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (compound 8) or a pharmaceutically acceptable salt thereof.
 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound as claimed in claim 1, 2, 3, 4, or 5 or a pharmaceutically acceptable salt thereof.
 7. A method for treating irritable bowel syndrome, comprising the step of administering to a subject in need thereof an effective amount of the pharmaceutical composition as claimed in claim
 6. 8. The method as claimed in claim 7, wherein the irritable bowel syndrome is treated by providing an antagonism to 5-HT7 receptors.
 9. The method as claimed in claim 7, wherein the irritable bowel syndrome is treated by inhibiting a pain induced by infection followed by stress.
 10. The method as claimed in claim 7, wherein the irritable bowel syndrome is treated by inhibiting a pain induced by chemically induced inflammation. 